CA2615946A1 - Pyrazolo pyrimidines useful as aurora kinase inhibitors - Google Patents

Abstract

The present invention provides compounds having the formula: (I) wherein A-B
together represent one of the following structures: (II) or (III) wherein one of ---- is a double bond, as valency permits; and R2, R4, X 1A, X2A, X1B, X2B, L1, L2, Y an Z are as defined in classes and subclasess herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., Aurora), and thus are useful, for example, for the treatment of Aurora mediated diseases.

Description

PYRAZOLO PYR1'1VIIDINES USEFUL AS A URORA .KINASE INHIBITORS
PRIORITY
[0001] The present application claims priority under 35 U.S.C. 119(e) to U.S.
Provisional Patent Application No.: 60/701,695 filed July 22, 2005, the entire contents of which are incorporated herein by reference.

BACKOROUND OF THE INVENTION

[0002] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.

[0003] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S.K., Hunter, T., FASEB J.
1995, 9, 576-596; Knighton et al., Science 1991, 253, 407-414; Hiles et aL, Cell 1992, 70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al., EMBO J.
1994, 13, 2352-2361).
[00041 In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function.
These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H202), cytokines (e.g., interleukin-i (IL-1) and tumor necrosis factor a(TNF-a)), and growth factors (e.g., granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0005) Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

[0006] The Aurora family of serine/threonine kinases plays an important role in cell proliferation. The three known mammalian family members, Aurora-A ("2"), B
("1") and C("3"), are highly homologous proteins responsible for chromosome segregation, mitotic spindle function and cytokinesis. Aurora expression is low or undetectable in resting cells, with expression and activity peaking during the G2 and mitotic phases in cycling cells. Elevated levels of all Aurora family members are observed in a wide variety of tumor cell lines. For example, the Aurora-2 protein has been found to be overexpressed in human colon cancer tissue [Bischoff et al., EMBO J. 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol. 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem. 1997, 272, 13766-137711. Aurora-2 has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is involved in protein phosphorylation events that regulate the cell cycle.
Specifically, Aurora-2 plays a role in controlling the accurate segregation of chromosomes during mitosis. Thus, Aurora inhibitors have an important role in the treatment of Aurora-mediated diseases.

[0007] Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. In particular, it would be desirable to develop compounds that are useful as inhibitors of Aurora, particularly given the inadequate treatments currently available for the majority of the disorders implicated in their activation.

SUMMARY OF THE INVENTION

[0008] As discussed above, there remains a need for the development of novel therapeutic agents and agents useful for treating disorders mediated by Aurora. In certain embodiments, the present invention provides novel compounds having the structure:

Ll--y-,L2'Z
BN
NJ~R2 (1) wherein A-B together represent one of the following structures:
--L L

X1A N X1B:1~ ~ N
~ R4-N N
~ / +
~/, J.\
x~ N R2 or 2B N R2;
wherein one of --- _. is a double bond, as valency permits; and R2, R4, X1A, X2A, X1B, X2B, L', L2, Y and Z are as defined in classes and subclasess herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., Aurora), and thus are useful, for example, for the treatment of Aurora mediated diseases.
100091 In certain other embodiments, the invention provides pharmaceutical compositions comprising an inventive compound, wherein the compound is present in an amount effective to inhibit Aurora activity. In certain other embodiments, the invention provides pharmaceutical compositions comprising an inventive compound and optionally further comprising an additional therapeutic agent. In yet other embodiments, the additional therapeutic agent is an agent for the treatment of cancer.
[0010] In yet another aspect, the present invention provides methods for inhibiting kinase activity (e.g., Aurora) activity in a patient or a biological sample, comprising administering to said patient, or contacting said biological sample with an effective inhibitory amount of a compound of the invention. In still another aspect, the present invention provides methods for treating any disorder involving Aurora activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

BRIEF DESCRIPTION OF THE DRAWING
100111 Figure 1 depicts exemplary biochemical assay data (IC50 values) for selected compounds of the invention. The compounds were evaluated in: (i) Aurora A kinase inhibition assay, (ii) Aurora B kinase inhibition assay, (iii) HCS
cell cycle assay and (iv) Phospho-Histone H3 HCS assay.
[0012] Figure 2 depicts an exemplary western blot experiment of compound B
using anti-Histone H3 and anti-phosphorylated Histone H3 antibodies as probes.
DEFINITIONS
10013J It is understood that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term "substituted" whether preceded by the term "optionally" or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, carbon and heteroatom substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment and prevention, for example of disorders, as described generally above.
Examples of substituents include, but are not limited to aliphatic;
heteroaliphatic;
alicyclic; heteroalicyclic; aromatic, heteroaromatic; aryl; heteroaryl;
alkylaryl;
alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio;
arylthio;
heteroalkylthio; heteroarylthio; F; Cl; Br; I; -NOZ; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; - or -GRGI wherein G is -0-, -S-, -NRoZ-, -C(=0)-, -S(=O)-, -SO2-, -C(=O)O-, -C(=O)NRGZ-, -OC(=O)-, -NRGaC(=O)-, -OC(=O)O-, -OC(=O)NRGZ-, -NRGZC(=O)O-, -NRG2C(=O)NRGa-, -C(=S)-, -C(=S)S-, -SC(=S)-, -SC(=S)S-, -C(=NR02)-, -C(=NRGa)O-, -C(=NRGZ)NRG3-, -OC(=NRo2)-, -NRG2C(-NR03)-, -NRG2S02-, -NRo2SO2NRo3-, or -SO2NRG2-, wherein each occunence of RGI, RGZ and RG3 independently includes, but is not limited to, hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, or alkylheteroaxyl moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
[0014] The term "stable", as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
[0015] The tenn "aliphatic", as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term "alkyl" includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as "alkenyl", "alkynyl" and the like.
Furthermore, as used herein, the terms "alkyl", "alkenyl", "alkynyl" and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, "lower alkyl" is used to indicate those alkyl groups (substituted, unsubstituted, branched or unbranched) having about 1-6 carbon atoms.
100161 In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain about 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-9 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents.
Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-l-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
100171 The term "alicyclic", as used herein, refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "alicyclic" is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups.
Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, -CH2-cyclobutyl, cyclopentyl, -CH2-cyclopentyl-n, cyclohexyl, -CH2-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.
100181 The term "cycloalkyl", as used herein, refers specifically to cyclic alkyl groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, heteroaliphatic or heterocyclic moieties, may optionally be substituted. An analogous convention applies to other generic terms such as "cycloalkenyl", "cycloalkynyl" and the like.
[0019] The term "heteroaliphatic", as used herein, refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, i.e., in place of carbon atoms. Thus, a 1-6 atom heteroaliphatic linker having at least one N
atom in the heteroaliphatic main chain, as used herein, refers to a C1.6aliphatic chain wherein at least one carbon atom is replaced with a nitrogen atom, and wherein any one or more of the remaining 5 carbon atoms may be replaced by an oxygen, sulfur, nitrogen, phosphorus or silicon atom. As used herein, a 1-atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain refers to -NH- or NR-where R is aliphatic, heteroaliphatic, acyl, aromatic, heteroaromatic or a nitrogen protecting group. Heteroaliphatic moieties may be branched or linear unbranched.
In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, any of the substituents described above.
[0020] The term "heteroalicyclic", "heterocycloalkyl" or "heterocyclic", as used herein, refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include but are not limited to saturated and unsaturated mono- or polycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl, thiofuranyl, pyrrolyl etc., which are optionally substituted with one or more functional groups, as defined herein. In certain embodiments, the term "heterocyclic" refers to a non-aromatic 5-, 6- or 7- membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen -heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyt, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
[0021] Additionally, it will be appreciated that any of the alicyclic or heteroalicyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
[00221 In general, the term "aromatic moiety", as used herein, refers to stable substituted or unsubstituted unsaturated mono- or polycyclic hydrocarbon moieties having preferably 3-14 carbon atoms, comprising at least one ring satisfying the Huckel rule for aromaticity. Examples of aromatic moieties include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, phenanthryl and anthracyl.

[0023] In general, the term "heteroaromatic moiety", as used herein, refers to stable substituted or unsubstituted unsaturated mono-heterocyclic or polyheterocyclic moieties having preferably 3-14 carbon atoms, comprising at least one ring satisfying the Huckel rule for aromaticity. Examples of heteroaromatic moieties include, but are not limited to, pyridyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl.
[0024] It will also be appreciated that aromatic and heteroaromatic moieties, as defined herein, may be attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety and thus also include moieties such as -(aliphatic)aromatic, -(heteroaliphatic)aromatic, -(aliphatic)heteroaromatic, -(heteroaliphatic)heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(alkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the phrases "aromatic or heteroaromatic moieties" and "aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, (heteroalkyl)heteroaromatic, and --(heteroalkyl)heteroaromatic" are interchangeable.
Substituents include, but are not limited to, any of the previously mentioned substituents resulting in the formation of a stable compound.
[0025] In general, the term "aryl" refers to aromatic moieties, as described above, excluding those attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety. In certain embodiments of the present invention, "aryl"
refers to a mono- or bicyclic carbocyclic ring system having one or two rings satisfying the Huckel rule for aromaticity, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
[0026] Similarly, the term "heteroaryl" refers to heteroaromatic moieties, as described above, excluding those attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety. In certain embodiments of the present invention, the term "heteroaryl", as used herein, refers to a cyclic unsaturated radical having from about five to about ten ring atoms of which one ring atom is selected from S, 0 and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, 0 and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
[00271 Substituents for aryl and heteroaryl moieties include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
[0028] The terms "alkoxy" (or "alkyloxy"), and "thioalkyl" as used herein refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom ("alkoxy") or through a sulfur atom ("thioalkyl"). In certain embodiments, the alkyl group contains about 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains about 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-4 aliphatie carbon atoms. Examples of alkoxy groups, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
[00291 The term "amine" refers to a group having the structure N(R)2 wherein each occurrence of R is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or the R groups, taken together, may form a heterocyclic moiety.
[00301 The term "alkylamino" refers to a group having the structure -NHR'wherein R' is alkyl, as defined herein. The term "aminoalkyl" refers to a group having the structure NHZR'-, wherein R' is alkyl, as defined herein. In certain embodiments, the alkyl group contains about 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains about 1-10 aliphatic carbon atoms.
In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.

[0031] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
[0032] The term "halogenated" denotes a moiety having one, two, or three halogen atoms attached thereto.
[0033] The term "haloalkyl" denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
[0034] The term "acyloxy", as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure -OC(O)Rx, wherein Rx is a substituted or unsubstituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
[0035] The term "acyl", as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure -C(O)Rx, wherein Rx is a substituted or unsubstituted, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
[0036] The term "imino", as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure -C(=NRx)RY, wherein Rx is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and Ry is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
[0037] The term "C1_6alkylene", as used herein, refers to a substituted or unsubstituted, linear or branched saturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, having a free valence "" at both ends of the radical.
[0038] The term "C2_6alkenylene", as used herein, refers to a substituted or urisubstituted, linear or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, having a free valence "-" at both ends of the radical, and wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule.
[0039] As used herein, the terms "aliphatic", "heteroaliphatic", "alkyl", "alkenyl", "alkynyl", "heteroalkyl", "heteroalkenyl", "heteroalkynyl", and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms "alicyclic", "heterocyclic", "heterocycloalkyl", "heterocycle" and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. Additionally, the terms "cycloalkyl", "cycloalkenyl", "cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocycloalkynyl", "aromatic", "heteroaromatic", "aryl", "heteroaryl" and the like, used alone or as part of a larger moiety, encompass both substituted and unsubstituted groups.
[0040] As used herein, the term "isolated", when applied to the compounds of the present invention, refers to such compounds that are (i) separated from at least some components with which they are associated in nature or when they are made and/or (ii) produced, prepared or manufactured by the hand of man.
[0041] The phrase, "pharmaceutically acceptable derivative", as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety that is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention.
Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
[0042] The term "Aurora-mediated disease" or "Aurora-mediated condition", as used herein, means any disease or other deleterious condition in which Aurora is known to play a role. The terms "Aurora-mediated disease" or "Aurora-mediated condition" also mean those diseases or conditions that are alleviated by treatment with an Aurora inhibitor. Such conditions include, without limitation, colon, breast, stomach, and ovarian cancer. The term "Aurora-mediated disease", as used herein, means any disease or other deleterious condition or disease in which Aurora is known to play a role. Such diseases or conditions include, without limitation, cancers such as colon and breast cancer.
[00431 The term "treating", as used herein generally means that the compounds of the invention can be used in humans or animals with at least a tentative diagnosis of disease. In certain embodiments, compounds of the invention will delay or slow the progression of the disease thereby giving the individual a longer life span.
[00441 The term "preventing" as used herein means that the compounds of the present invention are useful when administered to a patient who has not been diagnosed as possibly having the disease at the time of administration, but who would normally be expected to develop the disease or be at increased risk for the disease. The compounds of the invention will slow the development of disease symptoms, delay the onset of disease, or prevent the individual from developing the disease at all. Preventing also includes administration of the compounds of the invention to those individuals thought to be predisposed to the disease due to familial history, genetic or chromosomal abnormalities, and/or due to the presence of one or more biological markers for the disease.
100451 As used herein the term "biological sample" includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal-(e,g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. For example, the term "biological sample"
refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a.
mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated).
The biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid. The biological fluid may be obtained from any site (e.g.
blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g. a normal joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout or septic arthritis). The biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ. Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.
Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates. Although the sample is preferably taken from a human subject, biological samples may be from any animal, plant, bacteria, virus, yeast, etc. The term animal, as used herein, refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals. In certain exemplary embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig), An animal may be a transgenic animal or a human clone. If desired, the biological sample may be subjected to preliminary processing, including preliminary separation techniques.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE
INVENTION
[0046] As noted above, there has been increasing interest in recent years in the development of protein kinase inhibitors, particularly Aurora inhibitors, as therapeutic agents for the treatment of diseases/conditions involving protein kinase-mediated events. In one aspect, the present invention provides Aurora inhibitors.
[0047] Compounds of this invention include those generally set forth above and described specifically herein, and are illustrated in part by the various classes, subgenera and species disclosed herein. Additionally, the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.
[0048] 1) General Description of Compounds of the Invention [0049) In certain embodiments, the compounds of the invention include compounds of the general formula (I) as further defined below:

L'_Y'IL2'Z
A BN
N.~R2 wherein A-B together represent one of the following structures:
1 I, IA N XlB N
.' I ~ R4_N
/
~ N RZ or X2e N RZ;
and pharmaceutically acceptable derivatives thereof;
wherein one of ----- is a double bond, as valency permits;
RZ is hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
R4 is hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
XIA is NRl or -C(RX)-; wherein R' taken together with a moiety present on L1 may form an optionally substituted heterocyclic ring;

X2A is NR3 or -C(RxI) lA ( Xl) -; wherein one of X and X2A is -C R-, but not both;
XIB and X2B are -N- or -C(RX)-; whereby one of XIB and X2B is -C(RX')-, but not both;
wherein R' and R3 are independently hydrogen, a nitrogen protecting group, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; and e1 is hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
LI is a 2-8 atom heteroaliphatic linker having at least one N, 0 or S atom in the heteroaliphatic main chain;
L 2 is a 1-6 atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain;
Y is an alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; and Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety.

[0050] In certain embodiments, the following groups do not occur N
NX
simultaneously as defined: A-B together represent ~' N R2; XjA iS NR1 and X2A is CRxI or XIA is CRXI and XzA is NR3; Ll is -X(CHR")o-2-, wherein X
is 0, S, NH or NCl.4alkyl, and R" is H or CI_4alkyl; Y is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl or quinazolinyl; and L2-Z is lower alkyl (1-4 carbon atoms), cycloalkyl (3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8 carbon atoms), lower perfluoroalkyl (1-4 carbon atoms), lower acyloxy (1-4 carbon atoms; -OC(O)R), amino, lower mono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino (3-8 carbon atoms), hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), lower thioalkyl (1-4 carbon atoms), lower sulfinylalkyl (1-4 carbon atoms), lower sulfonylalkyl (1-carbon atoms), thiocycloalkyl (3-8 carbon atoms), sulfinylcycloalkyl (3-8 carbon atoms), sulfonylcycloalkyl (3-8 carbon atoms), sulfonamido, lower mono or dialkylsulfonamido (1-4 carbon atoms), mono or dicycloalkylsulfonamido (3-8 carbon atoms), mercapto, carboxy, carboxamido (-C(O)NHz), lower mono or dialkylcarboxamido (1-4 carbon atoms), mono or dicycloalkylcarboxamido (3-8 carbon atoms), lower alkoxycarbonyl (1-4 carbon atoms), cycloalkoxycarbonyl (3-carbon atoms), lower alkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbon atoms), lower alkynyl (2-4 carbon atoms).
[0051) In certain embodiments, the following groups do not occur N

simultaneously as defined: A-B together represent N\X2A N R2; XIA is NRI
and X2A is CRxI or X1A is CRXI and X2A is NR3; Rxl is hydrogen, halo, nitro, C1_ 6alkyl, C1_6alkoxy, -CONRaRb, -O(CHZ)õNRaRb, -(CH2)õNR.aRb or NRaRb; L' is -NHCH2-; Y-LZ-Z is pyridinyl, pyrimidinyl, indazolyl, dihydroisoindolyl, benzisoxazolyl, oxazolyl, imidazolyl, oxadiazolyl or thiazolyl each optionally substituted with halo, CI-6a1kyl, C1_6alkoxy, -O(CHz)õNR"Ry, -O(CHZ),OR", -NR"Ry, -(CH2)nNR"RY, -CH2OR", -COOR", -CONR"RY, -CH2SO2NRxRY, -SO2NRxRY, or optionally substituted phenyl; and R2 is pyridin-2-yl, C1-6alkyIpyridin-2-yl, Ct.
6alkylpyrrol-2-yl or CI.6alkylthiazol-2-yl; wherein Ra is H or Cl-4alkyl, R6 is C1-4alkyl, or Ra and Rb together for a 3-7-membered heterocyclic ring; and R" and RY
are independently H or C l.6alkyl.
[0052] In certain embodiments, for compounds of formula (I), no occurrence of Rl, R3, R4 or RXl is Q1, Q2 or Q3, wherein ]A 1B lA 1B 1C lA 1B lA 1B 1C
Q' is -(CR R )mC=C-(CR R )tR , -(CR R )mC=C-(CR R )tR , -C NORIO, or -X3RID wherein m is an integer from 0 to 3, t is an integer from 0 to 5, and X3 is a divalent group derived from azetidine, oxetane or a C3-4carbocyclic group;
Q2 i8 -(CRIARIB)mCLC-(CRIARIB)kR1E, -(CRtARIn)mC=C-(CRtAR1B)kRl>r wherein k is an integer from 1 to 3 and m is an integer from 0 to 3; and Q3 is -(CRIAR1B)tR1C, wherein t is an integer from 0 to 5 and the attachment point to Rlc is through a carbon atom of the Rlc group; wherein R IA and RIB
are independently H or CI-6alkyl; Rlc is an optionally substituted non-aromatic monocyclic ring, a fused or bridged bycyclic ring or a spirocyclic ring; RIE
is -NRlAR1D or -QRID' RID is RIF 1F IF ]F IF
, , -C(=0)R , -S02R , -C(=0)N(R )Z, - S02N(R. )2, or -COzRIF, wherein R1F is H, C1-6alkyl, -(CRIARIB)t(C6-10aryl) or -(CR1AR-1)I(4-10 membered heterocyclic).
[0053] In certain embodiments, the present invention defines particular classes of compounds which are of special interest. For example, one class of compounds of special interest includes compounds of formulae (IA) though (IA4):
L'_Y,1L2 'Z
R1 L~-Y~L2 -Z N~ N L1Y~L2=Z L1 -Y" L2=Z
N- N N
N N 'N ~ 2 N~ N R R4_N ~ R4-N.
N R2 , R3 , N R2 or N N R2 (TA1) W2) (IA) oA4) [0054) Another class of compounds of special interest includes compounds of formula3 (IB1) though (1114):

H LL2'Z Rxl Li-Y"IL2'Z L''Y\L2,z RX1 L1-YILZ'Z
N
N~ I NR N~ HN N~RZ
N
N HN ' Rx' ' H NJ~R2 ' Rxl or 'N N~R2 (iB1) (IB2) /~B3) (jB4) [0055] Another class of compounds of special~linterest includes compounds of formulae (ICl) through (Ic4);
2 W~~AIkj.Y,.L2 Z
R1 Wi,~AIk~Y,L~Z Rx1 N / 1LsR2 Rxl R3 (Ic') (Icz) WlrAIki,Y.L~Z Alk W~.~ l.YL2 Z
N' 'N Rxl R4-N -1- N
N RZ R4"N. ~ i Rx~ or N N R2 (C) O[C4) wherein WI is 0 or NRWI, where RWl is hydrogen, aliphatic,'heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and A1k1 is a Cl_ 6alkylene or Ca.6alkenylene moiety.
[00561 Another class of compounds of special interest includes compounds of formula (ID):

Rw~ ~,.-Alkj. .L~
R~ N Y Z
N ~N
N ~ I N %R2 Rxl o[D) wherein A1kt is a C1_6alkylene or C2_6alkenylene moiety; and RW1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; or RWl taken together with Rl may form a heterocyclic moiety.
[0057] Another class of compounds of special interest includes compounds of formula (IE):

Rwl -1 NAIkj'Y, L\

A BI

(JE) wherein A-B together represent one of the following structures:
.L ~L

~ R4-N ' ~

N\x~ N R2 or XZB N R2 wherein RWl is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; Alkl is a C1.6alkylene or C2.6alkenylene moiety; or Rwl taken together with a carbon atom present on Alkl may form a heterocyclic moiety.
[0058] Another class of compounds of special interest includes compounds of formula (IF):

Li ..-Y..W2II
-'+'W3' z A BN

(IF) wherein A-B together represent one of the following structures:
I ,L

/X1A ---N ~1B ~N
' ' I ~ R4-N :1: ~
NX~ N R2 or Xzg N Rz;
wherein W2 and W3 are independently absent, 0, NRW, CRWiRW2 or NRWCRWrRW2, where Rw is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and RWl and RW2 are independently hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic; with the proviso that W2 and W3 are not each absent and at least one of W2 and W3 is NRW or NRWCRW1RW2.

[0059] A number of important subclasses of each of the foregoing classes deserve separate mention; these subclasses include subclasses of the foregoing classes in which:
j00601 i) R2 is hydrogen, halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
[0061] ii) Rz is C1.3alkyl or C1.3alkoxy;
[0062] iii) R2 is methyl or -CF3;
[0063] iv) RZ is halogen;
[0064] v) R2 is hydrogen;
[0065] vi) XIA is NRl and X2A is -C(Rxl)-, or X2A is NR3 and XIA is -C(Rx)-, or XIB is N and X2B is -C(Rxl)-, or X2B is N and XlB is -C(Rx)-; wherein Rxl is hydrogen, halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
[0066] vii) XIA is NR' and X2A is _C(Rx')-, or X2A is NR3 and XIA is -C(Rx')-, or X1B is N and X2B is -C(Rx)-, or X2B is N and XIB is -C(Rxi) -; wherein Rxi is hydrogen, halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl moiety;
[0067] viii) Xl A is NR' and X2A is _C(Rx')-, or Xaa is NRs and Xin is -C(Rxt) -, or XIB is N and X2B is _C(Rx')-, or X2g is N and X'B is -C(Rxl) xl -; wherein R is hydrogen, halogen, or a lower alkyl, cycloalkyl, cycloalkenyl, lower heteroalkyl, heterocyclyl, aryl or heteroaryl moiety;
[00681 ix) XlA is NRl and X2A is -C(R.xl)-, or XzA is NR3 and X1A is -C(Rx)-, or XIB is N and X2B is _C(Rx')-, or X2B is N and Xln is -C(Rxi) xi -; wherein R is hydrogen, halogen, or a lower alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl moiety;
[0069] x) XIA is NR' and X2A is -C(Rx1)-, or X2A is NR3 and XIA is _C(Rx')-, or XIB is N and X2B is -C(Rxl)-, or X2B is N and XIB is -C(R.xl)-; wherein Rxl is hydrogen, halogen, C1_5alkyl, C1_5alkoxy, -COZH, -CO2C1_Salkyl, -CN or NO2;
[0070] xi) XIA is NRI and XaA is CH;

[00711 xii) XaA is NR3 and XIA is CH;
[0072] xiii) X'B is N and X2B is CH;
[0073] xiv) XZg is N and XIB is CH;

[0074) xv) XIA is NRI and X2A is -C(RX')-, or X2A is NR3 and XIA is -C(Rx')-, or X'B is N and X2B is --C(R.x')-, or X2B is N and XIB is -C(Rx')-; wherein Rx' is hydrogen, halogen, -CN, NOZ, -C(=O)R'A, -C(=O)OR'p', -C(=O)NR'AR'B, S(=O)2R'C, -P(=O)(R'C)2, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R''' and R'g are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; or taken together with the nitrogen atom to which they are attached form a 5-6-membered heterocyclic ring; and each occurrence of R'c is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
[0075] xvi) XIA is NR' and X2A is -C(RX1)-, or X2A is NR3 and X'A is -C(R.XlI-, or XIB is N and XZB is -C(Rx')-, or X2B is N and X'B is -C(Rx') x' J
-; wherein R is hydrogen, halogen, -NO2, -CN, -C(=O)OR'A, -S(=O)ZR'c, -P(=O)(R'C)2a alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl; wherein R'A is hydrogen or Ct.6alkyl; and each occurrence of R'o is independently C1_6alkyl;
, [0076] xvii) XIA is NR' and X2A is -C(Rx')-, or X2A is NR3 and XIA is -C(Rx')-or X1B is N and X2B is -C(RX')-, or X2B is N and X'B is -C(Rx)-; wherein RX' is hydrogen, halogen, NOZ, -CN, CI_5a1ky1 or C1_5alkoxy;
[0077] xviii) XIA is NH and X2A is -CH-, or X2A is NH and X1A is -CH-;
[0078] xix) X'A is NRI and XZA is --C(Rx')-, or X2A is NR3 and X'A is -C(Rx')-, or XIB is N and X2B is -C(RX')-, or XZB is N and X'$ is -C(RX)-; wherein RX' is F, Cl, Br or I;
[00791 xx) XIA is NR' and XM is -C(Rx')-, or X2A is NR3 and X'A is -C(RXl)-, or X'B is N and X2B is -C(Rx')-, or X2B is N and X'B is -C(Rx')-; wherein RX' is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl;

[0080] Xxi) XIA is NR' and X2A is -C(RXI)-, or X2A is NR3 and XIA iS -C(RXI)-, or XIB is N and XzB is -C(RXI)-, or XaB is N and XlB is -C(Rx)-; wherein RXI
is one of:
R1c R1A0 R1AS iN~,~ ~
p~- Jp- R1e l-lp ~

Rlc N
R1A0~ R1AS R1B' ~ p p Rlc R1Ao R1A5 N
pV,, pV+~ R1 g' ~V
py;
wherein V is 0, S or RIB; p is an integer from 0 to 6; and RIA is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -C(=0)N(RIB)2, -C(=O)ORIB; wherein each occcurrence of RIB and RIC is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; or R1B and RIc, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic moiety;
[0081] xxii) X1A is NRI and X2A is -C(R.X1)-, or X2A is NR3 and XIA is --C(Rx)-s or XIB is N and X2B is -C(RXl)-, or X2B is N and XIB is -C(Rxl)-; wherein Rxl is -CN, lower alkyl, lower alkynyl, -CO2R1D, or one of Rlc Rlc ~-_ ~- R1s' R18'"NM ps P
wherein p is an integer from 1 to 4; and RIA is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -C(=0)N(RIB)Z, -C(=0)ORIB;
wherein each occcurrence of R1B and Rlc is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl;
or RIB
and Rlc, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic moiety; and RID is hydrogen or lower alkyl;
[00821 XXlll) X1A iS NRI and XZA iS -C(RXI)-, or X2A lS NR3 and XIA iS -C(RXI)-, or XlB is N and X2B is -C(Rx)-, or X2B is N and XIB is -C(Rxl)-; wherein RXl is -CN, -C=-CH, methyl, -C02H, -COZMe, or one of:

HO~ ~ _ N HO
Hp 3 [0083] xxiv) XIA is NR' and X2A is -C(Rx')-, or X2A is NR3 and X'A is -C(RX')-, or X'B is N and X2B is -C(RX')-, or X2B is N and XIB is -C(Rx')-; wherein Rx' is aryl, heteroaryl or heterocyclyl;

[0084J xxv) X'A is NR' and X2A is -C(RX')-, or X2A is NR3 and X'a is -C(e')-a or X'B is N and X2B is -C(Rx')-, or X2B is N and X'B is -C(Rx')-; wherein Rx' is an aryl, heteroaryl or heterocyclyl moiety having one of the structures:

R1A)n ~ ~. (RIA)n or wherein the "A" cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; the "Het" moiety represents a fully or partially saturated or unsaturated 5- to 6-membered ring comprising 1-4 heteroatorns selected from N, and S; n is an integer from 0-6; and each occurrence of R'A is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl, -OR'$, -SR'B, -N(R'B)2, -SO2N(Rls)2a -SO2R'E,-C(-O)N(R's)2, halogen, -CN, -NO2,- -C(=O)OR'B, ' N(R.'B)C(=O)R'c or N(R'B)S02R'E; wherein each occcurrence of R'B and R'c is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of R'a, taken together with the nitrogen atom to which they are attached (e.g., N(R'B)2), form a substituted or unsubstituted heterocyclic moiety; R'E is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of RIA
may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring;
[0085] xxvi) XIA is NR' and XZA is -C(Rx')-, or XZA is NR3 and X'A is -C(RX')-, or X'B is N and XzB is -C(RX')-, or X2r' is N and X'B is -C(Rx')-; wherein Rx' is one of:

, N N i ~N
(R1A)n i (R7A)ri (R1A)n (RIA) (R'A)n ~ ~
(R1A)n (R1A) n/\' (RIA)n N

0 p O ~ \O

(R1A)n (R1A)n,\' ~ (R1A)n\ (RIA IT-N
)n' 4~
g (R1A)n'\ (R1A)n (RIA)n N~ (R'A)n~~; N
Nl~
R1D! N N R1D NR1D R7D (RIA) (RlA)n R1D R1A

R1D _N I (R1A)n~ ~ N
~ N N
R 'iD
-y (R1A)n (R1A)n "'z:zz (R~A)n i / / ~i p~~ (R1A)nON
O N
RiD O
r/~\~ R1 ~ O
(RIA)ri (R7A)n (R'A)n r"~
v Nj N
(R7q) R~~N 'c"'%O R N--~/O R\N S_O 0~5 O
R1A N s~ (R9A) ~~/N (R1A) ~~ (R1A)6 L. ( )n wherein each occurrence of RIA is independently hydrogen, alkyl, .cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl, -OR1B, -SR1B, N(R1B )2, -SO2N(RIB )a, -SOZR1E,-C(=O)N(R.1B)2, halogen, -CN, -NO2, -C(=O)OR'B, -N(RrB)C(=O)Rlc or N(R.IB)SO2R1E ; wherein each occcurrence of R IB and Rlc is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or R113 and Rlc, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; R ID is hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl or a nitrogen protecting group; and RlP- is lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; wherein n is an integer from 0 to 3 and r is an integer from 1 to 6;

[0086] XXvii) X1A is NRI and X2A is -C(Rx')-, or X2A is NR3 and XIA is -C(Rxl)-, or X1B is N and X2B is -C(Rxl)-, or X2B is N and XIB is --C(Rxl)-;
wherein Rxl is one of:

N 0 ~-- N
~R1A)n i , (R1A)n i N ~

(R1A) ~/ c' (R1A) ~ (R1A) ~ R1D R1A
CyJ-~ 'R1A)n ~ N ~-N
(R1A) N
n R1 D
wherein n, R IA and R ID are as defined in xlii) above;

[00871 xxviii) XIA is NR' -and X2A is -C(Rxl)-, or X2A is NR3 and XIA is -C(Rx')-, or Xla is N and XM is -C(Rx')-, or Xas is N and X'a is -C(Rxt) -; wherein Rxi is one of:
o'~ o i ~
1A ~
R1AQ ~R1B_N R1B-N R O ~
% 1c R1c R
R ID

1 O N O/~ N C R1A N~

~ R1A
,R1B
~N, R1C
N
RID N
$ ~ \ I ~
0 N C N N\
N' '' J
R1A N~,/
tR1A) R1A R1s ~
wherein n is 0-2; R IA is hydrogen or lower alkyl; each occcurrence of R1B
and RIc is independently hydrogen, lower alkyl, or R1B and RIc, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 5-6 membered heterocyclic moiety; R ID is hydrogen, or lower alkyl; RiE is hydrogen, or lower alkyl;
[0088) xxix) XIA is NRl and XZA is -C(Rxl)-, or X2A is NR3 and XIA is -C(Rxl)-, or X2$ is N and X2B is -C(Rxl)-, or X2B is N and XIB is -C(Rxl)-; wherein Rxl is one of:

i\ ~\ O i\ O S i \

R1A~ / R1B_(~ R1BN / ~/=
'' R1C ~ R1c R1E

R1A N R \N N N
\
1 ~/ ~ ~

/
N
R1c 1c N
R1C R, J
R1e N

wherein each occurrence of R1A is independently hydrogen or lower alkyl;
each occcurrence of Rls and RlC is independently hydrogen, lower alkyl, or R1B
and RlC, taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 5-6 membered heterocyclic moiety; RID is hydrogen, or lower alkyl; RIE is hydrogen, or lower alkyl;
[0089] xxx) XIA is NRl and XZA is -C(R.xl)-, or X2A is NR3 and 1A (Rxl)-X is -C , or X1B is N and X2B is _C(Rxl)-, or X2B is N and Xl$ is -C(R.x); wherein RX' is one of:

HO I\ H2N I~\ ~N p 0--)~
O
flQ H2N ~ /~s Me\ ~N \
~" Me O
OH
Me, Me Me O~ N N \
S ~ ~ ;J JJ CJ
Me Me O~
~---~ N ' N, N N
N\~ N\~
N CN'I~
N-<-~ N.~
N

[0090] xxxi) R' is hydrogen, -C(=O)RIA, -C(=O)ORIA, -C(=O)NRrARIB, S(=0)2RlC, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R1A
and RlB are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; or taken together with the nitrogen atom to which they are attached form a 5-6-membered heterocyclic ring; and each occurrence of Rlc is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
[0091] xxxii) R' is hydrogen, -C(=O)R1A, lower alkyl, lower alkenyl, heterocyclyl, aryl or heteroaryl; wherein R IA is hydrogen, or lower alkyl, aryl, or heteroaryl;
[00921 xxxiii) R' is hydrogen or lower alkyl;
[0093] xxxiv) R' is hydrogen;
[0094] xxxv) R' is lower alkyl;
[0095] xxxvi) R' is methyl, ethyl or isopropyl;
[0096] xxxvii) R' is -C1_6alkyl-GRGI wherein G is -0-, -S-, NRG2-, -C(=0)-, -S(=O)-, -SO2-, -C(=O)O-, -C(=O)NRG2-, -OC(=O)-, -NRG2C(=O)-, -OC(=O)O-, -OC(=O)NRGZ-, -NRG2C(=O)O-, -NRG2C(=O)NRG3-, -C(=S)-, -C(=S)S-, -SC(=S)-, -SC(=S)S-, -C(=NRGZ)-, -C(=NRGZ)O-, -C(=NRG2)NRG3-, -OC(=NRGa)-, -NRG2C(=NRG)-, -NRG2SOZ-, -NRGZSO2NRG3--, or -S02NRoz-, or ---GRGI is halogen, CN or N3; wherein each occurrence of Rr", RG2 and RG3 is independently hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety; and where G is -NRGa-, RGl and RG2 taken to gether with the nitrogen atom to which they are attached may form a 4- to 8-membered heterocyclic ring;
[00971 xxxviii) R' is -C1.6alkyl-GRGI wherein G is -0-, -S-, NRG2-, -C(=O)-, -S(=O)-, -SOZ-, -C(=O)O-, -C(=O)NRGZ-, -OC(=O)-, -NR 2C(=O)-, -OC(=O)O-, -OC(=O)NRGZ-, -NRo2C(=O)O-, -NRG2C(=O)NRG3-, -C(=S)-, -C(=S)S-, -SC(=S)-, -SC(=S)S-, -C(=NRoa)-, -C(=NRoa)O-, -C(=NRG2)NRG3 -OC(=NRGZ)-, -NjG2C(=VG3)- -NRG2SO2-, -NRG2SO2NRc'3-, or -S02NRc'2-, or-GRG1 is halogen, CN or N3; wherein each occurrence of RGI, RG2 and RG3 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; and where G
is -NRG2-, RG' and RGZ taken to gether with the nitrogen atom to which they are attached may form a 4- to 8-membered heterocyclic ring;
[0098] xxxix) R' is -C1-6alkyl-GRGI wherein G is -0-, -S-, -NRGa-, -C(=O)O-, -C(=0)NRGZ-, -S(=O)-, -SOZ- or -C(=0)NRGZ-SO2-, or -GRG1 is halogen; wherein each occurrence of RGi and R 2 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; and where G is -NRGZ-, Rol and RGa taken to gether with the nitrogen atom to which they are attached may form a 5- to 6-membered heterocyclic ring;
[0099] xl) Rl is one of:
Cl-salkyl CI-6alkyl Cl-sal\1 CI -6alkyl HO"I -6aly- HS/ RlA_N-" ),s E#O2C"' Cl-salkyl Cl-salkyl O C1.6alkyi MeS-" \X MeS~ MeO~
O
wherein the C1-6alkyl moiety is optionally substituted; and RIA and R1B are independently hydrogen or lower alkyl;
[01001 xli) R' is one of:

CI~H2)2-3 HO~H2)2-' HS/-H2)2~ RIA-N~H2)2~ Et02C~H2)2 ~ s r' R1 s (CH2)2-3 (CH2)2-3 0 ' (CH2)2-3 MeS~ MeS'~ MeS;--' p 0 11 wherein RIA and Rl B are independently hydrogen or lower alkyl;
[01011 xlii) R' is one of:
(CH2)2 (CH2)3 (CH2)2 (CH )3 (CH2)2 (CH2)3 / \ / '' 1A._ ~ ~ 1A - \
HO ~ HO' H2N' ss'r H2N~ ~ R R~s +'''s R-RlB
wherein R IA and R' s are independently hydrogen, methyl or ethyl;
[0102] xliii) R' is -C1_6alkyl-NRG1RG2 wherein RGl and RG2 taken together with the nitrogen atom to which they are attached may form an optionally substituted 5-to 6-membered heterocyclic ring;
\ ,1~al ~
R
N
Wn [0103] xliv) Rl is wherein n is 0, 1 or 2; R is hydrogen, halogen, lower alkyl or lower alkoxy; and X is 0 or NR' where R' is hydrogen or lower alkyl;
[0104] xlv) R' is:

Cl-salkyl CI-6alkyl Cl-aalky) CI-6alkyl j1-saI\I
N, Ni N,' N~ ~~' N
Q CJ ~ EN) C0) R
/1 salkI RO ,l sal~l Ca salkyl CI sal~l CI_salk~
RON r+'f N rr'r N N
I \~ RO ~ 1 RO ' ~ RO '( N
l ~~' N 0 R
wherein the C1_6alkyl moiety is optionally substituted; and R is hydrogen or lower alkyl;
[01051 xlvi) R' is:

(CH2)2 (CH2)2 NCH~ N~CH2)~ N
N~ 0 OH OH
(CH2)2 N%CM2)~ N%CHZ)2 N
UOH ~CH2)~
CN
C0) OH
[0106] xlvii) R' is:
N (CH2)2 N~CH2)~
N~CH2)2 N (CH2)3 ~ ~ 0 C) [0107] xlviii) R' is -C1_6alkyl-C(=O)-NRG1Ro2 or -Ct_6alkyl-C(=O)-NHSO2R03 wherein Rot and Ro2 taken together with the nitrogen atom to which they are attachetl may form an optionally substituted 5- to 6-membered heterocyclic ring; and RG3 is lower alkyl;
[0108] xlix) R' is:
O~ Ci_Baik r O Ct.6alk~ O, C1_salk' O Qi_salk j OC~_sal\r O Ci.eal k~
'~' ' ' N N

Q ~ ON C NJ COJ H ~~,S:~ ~3 R
0 Csal\S d,~ ~y C1.6alka r O C, _safkyl O Cl .6alkyl 0 Cl.Balky yl ~ ~ r ~ ~r <- ~~R OR ~ OR N~ OR CO~ OR
R
wherein the C1_6alkyl moiety is optionally substituted; R is hydrogen or lower alkyl;
and RG3 is lower alkyl;
[0109] 1) R' is:

O' --CH2\s O\\ ~CH2\r O~ N N
j' 'CHZs O'\ ~,CHZs 0'\ /CHz '~' 'l" O 'N~' y 0 v q OH '' OH OH
OH
O' õCH2\s O' 'CH2's O' 'CHz 0 CH2 ~ ~N'" N' r HN,Me UUH (N~ C0~ O, =0 I a [0110] li) Compounds of subsets vi) through xxx) wherein Rl has the definition given in subsets xxxi)- 1);
[0111] lii) R3 is hydrogen, -C(=O)R3A, -C(=O)OR3A, -C(=O)NR3AR3B, S(=O)2R3C, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R3A
and R3B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; or taken together with the nitrogen atom to which they are attached form a 5-6-membered heterocyclic ring; and each occurrence of R3C is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
[0112] liii) R3 is hydrogen, -C(=O)R3A, lower alkyl, lower alkenyl, heterocyclyl, aryl or heteroaryl; wherein R3A is hydrogen, or lower alkyl, aryl, or heteroaryl;
[0113] liv) R3 is hydrogen or lower alkyl;
[0114] lv) R3 is hydrogen;
[0115] lvi) R3 is lower alkyl;
[0116] lvii) R3 is methyl, ethyl or isopropyl;
[0117] lviii) R3 is -C1.6alkyl-GRG3 wherein G is -0-, -S-, -NR ~-, -C(=0)-, -S(=O)-, -SO2-, -C(=O)O-, -C(=O)NRG4-, -OC(=O)-, -NRG2C(=O)-, -OC(=O)O-, -OC(=O)NR 4-, -NRG4C(=O)O-, -NRG4C(=O)NRG4-, -C(=S)-, -C(=S)S-, -SC(=S)-, -SC(=S)S-, -C(=NRG4)-, -C(--NRG4)O-, -C(=NR 2)NRGS-, _OC(--NRG4)-, -NRo~C(=NRoS)-, -NRG4SO2-, -NR 4SOZNRGS-, or -SO2NRG4-, or-GRG3 is halogen, CN or N3; wherein each occurrence of RG3, RG~ and RG5 is independently hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety; and where G is -NR04-, RG3 and RG4 taken to gether with the nitrogen atom to which they are attached may form a 4- to 8-membered heterocyclic ring;
[01181 lix) R3 is -C1_6alkyl-GRG3 wherein G 1S -0-, -S-, -NRG4-, -C(=O)-, -S(=O)-, -SOZ-, -C(=O)O-, -C(=O)NRG4-, -OC(=O)-, -NRG4C(=O)-, -OC(=O)O-, -OC(=O)NRG4-, -NRG4C(=O)O-, -NRG4C(=O)NRG5-, -C(=S)-, -C(=S)S-, -SC(=S)-, ..
SC(=S)S-, -C(=NRG4)-, -C(=NRG4)O-, -C(=NRG4)NRG5-, -OC(=NRG4)-, -NRG4C(=NRG5)-' -NRG4SO2-, -NRG4SO2NRGS-, or -SO2 NRG4-, or -GR03 is halogen, CN or N3; wherein each occurrence of RG3, RG4 and RG5 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; and where G
is -NRG4-, RG3 and RG4 taken to gether with the nitrogen atom to which they are attached may form a 4- to 8-membered heterocyclic ring;
101191 lx) R3 is -C I-6alkyl-GRG3 - wherein G is -0-, -S-, -NR -, -C(=0)O-, -C(=O)Ne-, -S(=0)-, -SO2- or -C(=O)NRG4-SO2-, or -GRG3 is halogen; wherein each occurrence of RG3 and RG4 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; and where G is NR.G4-, RG3 and RG4 taken to gether with the nitrogen atom to which they are attached may form a 5- to 6-membered heterocyclic ring;
[0120] lxi) R3 is one of:

C1.6alkyl C1_6alkyl j-salk\yl Cl_sal\I ji sal\Yl CI 'X He 'cs's HS R3p'-N c+'' EtOZC ss' ~3B

C1_6alkyl Csalkyl O CI-6alkyl MeS~ Y_ MeS~ Meo~

wherein the C1_6alkyl moiety is optionally substituted; and R3A and R3B are independently hydrogen or lower alkyl;

[01211 lxii) R3 is one of CH (CH2)2-3 (CH2)2-3 (CH2)2\
~ 2)2 s jH2)2',s HS.~ R3n_N'~ EtO2C~
CI d' HO R38 (GH2)2-3 (Cf-12)2-3 O (CH2)2-3 MeS'~~ MeS;" ~ MeO~

wherein R3A and R3B are independently hydrogen or lower alkyl;
10122] Ixiii) R3 is one of:

(CH2)2 (CH2)3 (CH2)2 (CH2)3 (CH2)2 (CH2)3 HO~ HO' \r*' H2N' H2N~ o+~ R3A._N iass R3A-N" ~,a'' wherein R3A and R3B are independently hydrogen, methyl or ethyl;
[0123] lxiv) R3 is -Cl-6alkyl-NRo'RG2 wherein Rol and RGa taken together with the nitrogen atom to which they are attached may form an optionally substituted 5-to 6-membered heterocyclic ring;
N
R\ jI-salkyl [01241 lxv) R3 is Pn wherein n is 0, 1 or 2; R is hydrogen, halogen, lower alkyl or lower alkoxy; and X is 0 or NR' where R' is hydrogeii or lower alkyl;
[0125] lxvi) R3 is:

N
NCi.sal\~ NCl sal ~ NCI_salk~ CI-6alkyl ,,.sal~
Q CN N C0) R
CI-6alkyl Cl_salkyl C1-6alkyl C1-6alkyl CI-6alkyl RON~ R\ N~ N~ rN~ N~' v v RO~ RO' ) RO
J
N O
R
wherein the CI-6alkyl moiety is optionally substituted; and R is hydrogen or lower alkyl;

[0126] lxvii) R3 is:

(CH2)2 (CH2)2 N/(CH2)2 N~(CH2)~ N N

OH OH
(CH2)2 (CHa)2 (CH2)2 (CH2)2 N N N

aOH \N~
OH O
[0127] lxviii) R3 is:
N JCH2)~ N~CH2)~ N (CH2)2 N~CH2)3 101281 0 0 a 0 [0129] lxix) R3 is -C1_6alkyl-C(=O)-NRo'Ro2 or -C1_6alkyl-C(=O)-NHSO2Ro3 wherein Ro1 and RGZ taken together with the nitrogen atom to which they are attached may form an optionally substituted 5- to 6-membered heterocyclic ring; and RG3 is lower alkyl;
[0130] lxx) R3 is:
O, CI_sal\ O C~.eal~ 0,, C,sal~ O,~ C1fialk\ O' C1_fial\f 0 C1T
_salk~
N~ O N~ N~ N~
CJ () ( HNsS'RG3 N O O O
R

'S
O Cl_sa~\r Oy CT _6a1k s O'' Ci_Bals O, C,8al\f O-' Cl_saik\
S
"\OR v-OR ') OR C)OR C)OR

R
wherein the C1_6alkyl moiety is optionally substituted; R is hydrogen or lower alkyl;
and R G3 is lower alkyl;
[01311 lxxi) R3 is:

O CH2 O~CH2 O CH2 O CH2 O CH2 y s N \~' ~/ ~s y ~/ s ,. \ C) N
~ v q OH OH OH OH
O CH2's O CHz O CHz' O CH2 '' ~.' 's HN, Me v OH N) (0N) O'S~O
[0132] lxxii) Compounds of subsets vi) through xxx) wherein R3 has the definition given in subsets lii)- lxxi);
[0133] lxxiii) R4 is hydrogen, -C(=O)R4A, -C(=O)OR4A, -C(=O)NR4AR4a, -S(=O)2R4C, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R4A
and R4B are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; or taken together with the nitrogen atom to which they are attached form a 5-6-membered heterocyclic ring; and each occurrence of R is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
[0134] lxxiv) R4 is hydrogen, -C(=O)R4A, lower alkyl, lower alkenyl, heterocyclyl, aryl or heteroaryl; wherein R4A is hydrogen, or lower alkyl, aryl, or heteroaryl;
[0135] lxxv) R4 is hydrogen or lower alkyl;
[0136] lxxvi) R4 is hydrogen;
[0137] lxxvii) R4 is lower alkyl;
[0138] lxxviii) R4 is methyl, ethyl or isopropyl;
[01391 lxxix) R4 is -C1_6alkyl-GRG3 wherein G is -0-, -S-, -NRG4-, -C(=0)-, -S(=O)-, -SO2-, -C(=O)O-, -C(=O)NRG4-, -OC(=O)-, -NRG2C(=O)-, -OC(=O)O-, -OC(=O)NR I-, NRG4C(=O)O-, NRG4C(=O)NRG4-, -C(=S)-, -C(=S)S-, -SC(=S)-, -SC(=S)S-, -C(=NRG4)-, -C(=NRG4)O-, -C(=NRG2)NRGS-, -OC(=NRo4)-, NRG4C(=NR G5)-, -NR G4SO2-' -NRG4SOZNRGS-, or -SO2NRG4-, or _GRG3 is halogen, CN or N3; wherein each occurrence of RG3, RG4 and RG5 is independently hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety; and where G is -NRG4-, RG3 and RG4 taken to gether with the nitrogen atom to which they are attached may form a 4- to 8-membered heterocyclic ring;
[0140] lxxx) R4 is -C1_6alkyl-GRG3 wherein G is -0-, -S-, -NRG4-, -C(=O)-, -S(=O)-, -SO2-, -C(=O)O-, -C(=O)NRG4-, -OC(=O)-, -NRG4C(=O)-, -OC(=O)O-, -OC(=O)NRO4-, -NRG4C(=O)O-, -NRG4C(=O)NRGS-, -C(=S)-, -C(=S)S-, -SC(=S)-, -SC(=S)S-, -C(=NRG4)-, -C(--NRG4)O-, -C(=NRG4)NRG5-, -OC(=NRG4)-, -NRG4C(=NRGS)-, -NRG4SO2-, -NRG4SO2NRGS-, or -SO2NRG4-, or -GRG3 is halogen, CN or N3; wherein each occurrence of RG3, RG4 and RGS is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; and where G
is -NRG4-' RG3 and RG4 taken to gether with the nitrogen atom to which they are attached may form a 4- to 8-membered heterocyclic ring;
[0141] lxxxi) R4 is -C1_6alkyl-GRG3 wherein G is -0-, -5-, NRG4-, -C(=O)O-, -C(=O)NRG4-, -S(=0)-, -SO2- or -C(=O)NRG4-SO2-, or -GRG3 is halogen; wherein each occurrence of RG3 and RG4 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; and where G is -NRG4-, RG3 and RG4 taken to gether with the nitrogen atom to which they are attached may form a 5- to 6-membered heterocyclic ring;
[0142] lxxxii) R4 is aryl or heteroaryl;
[0143] lxxxiii) R4 is one of:

(R4A)q (R4A)q (R4A)q (R4A)q (RaA)q ~-~ N \N 1 ~ (I~iN ~
U ~ CNJ 'NJ 0 (R4A)q (R4A)q (R4A )q (R4A)q (R4A)q i -h~~.
CSJ ~NJ ~ 0f S
~as ' (R4A)q (R4A)q (R4A) q (RN)I (R4A)q N~I-1,''~ N~
N-p,J SJ N N
(R4A)q R4B Ra6 //-I N-N
N~ \/\ R4A' \N/' ~~ (R4A)q N (R4A)q' R4B ~ fV
N-N N-N

R4A-j -S'~q- R4A'-~O>~ .
~
wherein q is an integer from 0 to 3; each occurrence of R4A is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR4C, -SR4c~ NR4BR4C' -SO2WBR4C, -C(-O)NR4BR4C, halogen, -CN, -NOZ, -C(=O)OR4C, -N(R4B)C(=0)R4C, wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, -heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R4B and R4C taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring;
(R4A)qN

~ ~.
[01441 lxxxiv) R4 is [01451 lxxxv) R4 is [0146] lxxxvi) R4 is one of:

Cl_salkyl Cj~alkyl C1_6alkyl Cl_salkyl Cl_salkyi CI~ H0~ HS~ \d,r R4A-N"' Et02C

C1_6alkyl Cl.6alkyl O C1-6alkyi MeS/ MeS/ \/, MeO/
O
wherein the C1_6alkyl moiety is optionally substituted; and R4A and R4B are independently hydrogen or lower alkyl;

[0147] lxxxvii) R4 is one of:

(CH2)2-3 (CH2)2-3 (CH2)2-3 CI~H2)2-3 HO~H2)2-3 HSX x R4A-N~ X, Et02C

(CH2)2-3 (CH2)2-3 e~S (CH2)2 MeS~ MeS~ M

O
wherein R4A and R4B are independently hydrogen or lower alkyl;
[0148] lxxxviii) R4 is one of:
(CH2)2 (CH2)3 (CH2)2 (CH2)3 (CH2)2 (CH2)3 HO~ i~ HO' \c~ H2N' H2N-' R4A-N' R4A--N-a4B R4B

wherein R4A and R4B are independently hydrogen, methyl or ethyl;
[0149] lxxxix) R4 is -C1-6alkyl-NRo1RG2 wherein Rc" and RG2 taken together with the nitrogen atom to which they are attached may form an optionally substituted 5- to 6-membered heterocyclic ring;

R\ jl'sal kyl N

101501 xc) R4 is Wn wherein n is 0, 1 or 2; R is hydrogen, halogen, lower alkyl or lower alkoxy; -and X is 0 or NR' where R' is hydrogen or lower alkyl;
[0151] xci) R4 is:

C_saikyl Cl_6alkyl CI_6alkyl CI_6alkyl C1_6aikyl ~,s j Ni ~ i N N~ N~
v 0 N ~ CN cOIJ

R
C1-salkyl RO C1_6alkyl Cl_fialkyt C1_6alkyl NCI-sal\~
RO N~ \N~ N~ e,sr rN~
~ v RO ~ RO RO
N O
R
wherein the C 1-6alkyl moiety is optionally substituted; and R is hydrogen or lower alkyl;
[0152] xcii) R4 is:

(CH2)2 (CH2)2 (CH2)2 (CH2)' N~ N~ N~

0 'l'--/>
OH OH
(CH2)2 N(CH2)2 N(CH2)2 N~CHZ)2 UOH C0) ~N~ [0153] xciii) R~ is:

N~CHz)~ N~CHz)3 N~CH2)2 ~CH~~
N +''s v v U a .
, [0154] xciv) R4 is -C1_6alkyl-C(=4)-NRG' RG2 or -C1_6alkyl-C(=0)-NHSOaRo3 wherein RG' and RGZ taken together with the nitrogen atom to which they are attached may form an optionally substituted 5- to 6-membered heterocyclic ring; and RG3 is lower alkyl;
[0155] xcv) R4 is:
p Cj_salk\f O~ C1_6aiks O Cisal\s O,~ Cl _sal\r O'' Cl_sals O CI_salkyl 0~ d ~ V3, P ;
HN~ ,RGS
O ~ (N) (N
O S O
N O
R
O CI_sal\ Q~~~-sa~, O~ C,_sal\r O~ Cl_sal\~ O~ Ci sal~
J
J
r '~ '~ '~ '~
<" ~OR OR ~ OR ~N~ OR CN J OR
N O
i R
wherein the C1.6alkyl moiety is optionally substituted; R is hydrogen or lower alkyl;
and RG3 is lower alkyl;
[0156] xcvi) R4 is:

O'\ /CH2\s O'\ /CH2,~s O'' ~CH2\r OyCHp O'\ CH2 'i' ~' ~" "

0 ,~N~ N
~"
OH %OH OH OH
O CHz O CH2 O CHz O CH2 , N N- Y
HN,S,Me v 'OH N" ~O p' 'O

[01571 xcvii) Compounds of subsets vi) through xxx) wherein R4 has the definition given in subsets lxxiii)- xcvi);
101581 xcviii) Ll is Wl-Alkl-; wherein W1 is 0, S, NRWI or -C(=O)NRWI
where RWl is hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alkl is a substituted or unsubstituted Cl.
6alkylene or C2.6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=0)-, -C(=O)NRL1A_, _OC(=O)-, -OC(=O)NRL1A_, _NRLIANRLIB_~ 3qRLIANRLIBC(=0)-, _ NRL1AC(~O)-, -NR~IACOa_, _NRL1AC(_O)NRLls_, -S(=O)-, -SO2-, -NRLIASO2-, -SO2NRLIA-, -NRL1ASO2NRL1B-, -0-, -S-, or -NRL1A-; wherein each occurrence of RL1A and RLIB is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
101591 xcix) L' is -W i-Alkl-; wherein W 1 is 0, S, NRW 1 or -C(=O)NRW 1 where RW1 is hydrogen, lower alkyl, C3_5cyc1oalkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alkl is a substituted or unsubstituted C1.6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=0)C(=0)-, -C(=O)NRL1A-, -OC(=0)-, -OC(=O)NRL1A-, _NRLIANpLIB_ -NRL1ANRLIBC(=O)-, -NRLIAC(=O)-, -NRLIACO2-, -NRLIAO(! O)NRL1B_, _S(=O)_, -SO2-, -NRLIAS02-j -SONRL1A-, _~LIASOZqRLIB_, -O_, -S-, or -NRL1A_; wherein each occurrence of RLIA and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
(01601 c) Compounds of subset xcix) above wherein Wl is S;
[01611 ci) Compounds of subset xcix) above wherein Wl is 0 or NRWI;

[0162] cii) L' is -O-Alk1-; wherein A1k1 is a substituted or unsubstituted C2alkylene chain;
[0163] ciii) L' is -0-cyclopropyl-;
[0164] civ) L1 is -O-CHaCH2-;
[0165] cv) L' is NRWI-AIkl-; wherein RWl is hydrogen, lower alkyl, C3.
6cycloalkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alkl is a substituted or unsubstituted CZ.6alkylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -S(=0)-, -SO2-, -0-, -S-, or -NRL1A-; wherein RLIA is hydrogen or lower alkyl;
[0166] cvi) Ll is NRW'-Alkt-; wherein Rw1 is hydrogen, lower alkyl or lower heteroalkyl; and Alk, is a substituted or unsubstituted C2alkylene chain;
[0167] cvii) Ll is -NH-cyclopropyl-;
[0168] cviii) L1 is NH-CH2CH2-;
[0169] cix) Ll is NH-CH2CF2-;
[0170] cx) LI is NH-CH2CH[(CH2)pORW2]-; wherein p is 1 or 2 and RW2 is hydrogen or lower alkyl;
[0171] cxi) Ll is NH-CH2CH(CH2OH)-;
[0172] cxii) Ll is NH-CHZCH(CHaCH2OH)-;
[01731 cxiii) L1 is NRWI-Alkl-; wherein RWl is lower heteroalkyl; and Alk, is a substituted or unsubstituted C2alkylene chain;
[01741 cxiv) L1 is NRWI-Alki-; wherein e1 is -(CH2)2NRW2RW3; Alkl is a substituted or unsubstituted C2alkylene chain; and RWa and e3 are independently hydrogen or lower alkyl;
[01751 cxv) LI is NRW'-(CH2)2-; wherein e1 is -(CH2)2NR i'2 RW3; and RW2 and RW3 are independently hydrogen or lower alkyl;
[0176] cxvi) L' is NRWI-(CHa)2-; wherein Rwl is -(CH2)2NMe2;
[0177] cxvii) L1 is NRWI-AIkl-; wherein R i'l together with a carbon atom present on Alkl forms an optionally substituted 5- to 6-membered heterocyclic moiety;
[0178] cxviii) Ll has the structure:

N
L

RAIk1 wherein RA11e1 is hydrogen, halohen, hydroxy, CN, nitro, lower alkyl, lower alkoxy, aryl, or heteroaryl;

[01791 cxix) Ll has the structure:
'~1 N
\-;
[0180] cxx) L1 has the structure:

N-'~.
RAIk1;
wherein RAlkl is hydrogen, halohen, hydroxy, CN, nitro, lower alkyl, lower alkoxy, aryl, or heteroaryl;
[0181) cxxi) Ll has the structure:
A N \

a [0182] cxxii) XIA is NRl and L' is NR't'1-Alkl-; wherein Ru'1 together with R' forms an optionally substituted 5- to 6-membered heterocyclic moiety;
[0183] cxxiii) Compounds of subset cxxii) above wherein R'r''1, R' and the pyrazolo pyrimidine to which they are attached form the structure:

~\~N
N
N~ N' ' Rxl wherein R is hydrogen, halohen, hydroxy, CN, nitro, lower alkyl, lower alkoxy, aryl, or heteroaryl;
[0184] cxxiv) Compounds of subset cxxii) above wherein RWI, R' and the pyrazolo pyrimidine to which they are attached form the structure:
R
N%4.
N N
N ~ ~
~ NJ
~
[0185] cxxv) Compounds of subset cxxii) above wherein Rw1, RI and the pyrazolo pyrimidine to which they are attached form the structure:

N N

N ;
[0186] cxxvi) L1 is -C(=O)NRW1-Alk1-; wherein RW1 is hydrogen or lower alkyl; and Alkl is a substituted or unsubstituted Cialkylene moiety;
[0187] cxxvii) Ll is -C(=0)NH-CH2-;
[0188] cxxviii) Y is a saturated or unsaturated cyclic ring system optionally comprising one or more heteroatoms selected from S, N and 0;
101891 cxxix) Y is a saturated or unsaturated monocyclic cyclic ring system optionally comprising one or more heteroatoms selected from S, N and 0;
[0190] cxxx) Y is a cycloalkyl, cycloalkenyl, heterocylic, aryl or heteroaryl moiety;
[0191] cxxxi) Y is a 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl, 5-6 membered heterocylic, 6-membered aryl or 6-membered heteroaryl moiety;
[01921 cxxxii) Y is one of:

(RY1) (RY1)q (RY1)9 (RY1)Q (RY1)q N1 L~
lNJ o (RYt)q (RY1)q (RY1?q RY1 RY7 S~ N ~N 0 S

Rv1 RyR1 RY1 (RY1)9 RY1 ~,-1~,~ N~ 1~,~
N~ ~~ N N 'N
~ (Ryl) S RY2 RY2 N-N
q "'' N~~1/'zrz N '' N
.N~ RY1N~N RY1~~N
~~ri' RY2 ww ,wv N-N N-N
~,~5>'~= ~~o>'~ ;
wherein q is an integer from 0 to 3; each occurrence of RYl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORv3, -SRY3, -NRYZRY3, -SO2NRY2RY3, -C(=O)NRY2RY3, halogen, -CN, NOZ, -C(=O)ORY3, -N(Rv2)C(=O)RY3, wherein each occcurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R~2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring;
[01931 cxxxiii) Y is one of:
N
(RY~)(RYt)q Rvl Ryl q N
N~~ Ryl N
o N-N N-N N//- NA
wherein q and RYt are as defined directly above;
[0194] cxxxiv) Y is one of:

~RY1) q ~RY1~q Ryl RY' O-N N=N
\N~ yN
S

Ryl Rvl (RYi)4 N N ~
N\~ N-N N-N
"'?YI)qe .
~
wherein q is 0-3; and RY1 is hydrogen, halogen or lower alkyl;
[0195] cxxxv) Y is one of:
N_N
s aN ~ N
N\~
N S
~a.

~N
N k N
N-N N-N

~. s >
[0196] cxxxvi) Y is one of:

N N N~ N ~
[0197] cxxxvii) Y is:
N
[0198] cxxxviii) Y is:

~. , [0199] cxxxix) Y is:

N//~-- N~
~~ .
[0200] cxl) Y is:

_R'Y1 ~ ~ .

wherein at least one RY1 is halogen, the other is hydrogen or halogen;
[02011 cxli) Y is:

j RY1 wherein at least one RY' is fluoro, the other is hydrogen or fluoro;

[0202] cxlii) L2 is NRL2A- or a substituted or unsubstituted C1_6alkylene or C2_ 6alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=O)-, -C(=O)NRL2A_' -OC(=O)-, -OC(=O)NRL2A_, -N,~L2AIqRL2B-, -NRL2ANRL2BC(=O)-, -NRL2AC(=O)-' -NRL2ACO2-, -NRL2AC(=O)NRL2B-, -S(=O)-, -SO2--, -NRL2ASO2-, -SO2NRL2A-, -NRL2ASOzNRL2B L2A
-, -0-, -5-, or -NR -; wherein each occurrence of RL2A, RL2B, RL2C and RL2D is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
[0203] cxliii) L2 is NRL2A- or a substituted or unsubstituted C1_6alkylene or CZ_ 6alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=O)-, -C(=O)NRL2A-, -OC(=O)-, -OC(=O)NRL2A-, -NRL2ANRL2B-, -NRL2ANRL2BC(=O)-, -NRL2AC(=O)-, -NRL2AC02-, -NkL2AC(=O)NRL2B-, -S(-O)-, -SO2-, -NRL2ASO2-, -SO2NRL2A-, -NRL2AS02NRL2B L2A
-, -0-, -S-, or -NR -; wherein each occurrence of RL2A, RL2B, R L2C and RL2D is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
[0204] cxliv) L2 is -(CH2)mNRL2A(CH2)m-, -(CH2)mC(=O)NRL2A(CH2)m ~ -(CH2)mOC(=O)NRL2A(CH2)m-, -(L-,H2)mNRL2ANRL2B(CH2)m-, (CH2)mNRL2ANRL2BC(=0)(CH2)m-, -(CH2)mNRL2AC(=O)(CH2)m-' (CH2)mN-RL2AC(=O)O(CH2)m-, -(CH2)mNNRL2AC(_O)NRL2B(CH2)m-' (CH2)mNRL2AC=O)~L2BCRL2CRL2D(CH2)m_, (CH2)mCR~CRlL2DC(=O)NRL2B(CH2)m-, -(CH2)mNRL2AS02(CH2)m , _ (CH2)mSO2NRL2A(CH2)m-, -(CH2)mNRL2ASO2NRL2B(CH2)m-; wherein each occurrence of m is independently 0-4; and each occurrence of RL2A, R L2B, RL2C
and RL2D is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
[02051 cxlv) L2 is NRL2A-, -C(=O)NRL2A-, -OC(=O)NRL2A_, -NRL2ANRL2B_, _ NRL2ANRL2BC(_p)_, _NRL2AC(=O)_, _NRL2AC02_, _NRL2AC(=O)NRLa$_, _ NRL2AC(=O)NRL2sCRL2CRL2D' _CRL2cRL2DC(4O)NRL2H, 'NRL2ASO2-, -SO2NRL2p'-, _NRL2ASO2NRL2B_? wherein each occurrence of RL2A, RL2B' RL2C and RL2D is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;

[02061 cxlvi) L2 ls NRL2A-, -C(=O)NRL2A-, -NRL2AC-O)-, -OC(=0)NR.L2A
-, -_ NFL2ACO2-, -NRL2AC(=O)NRL2B_' -~L2AC(=O)NRL2BCRL2CRL2D or CRL2CRL2DC(=O)NRL2B L2A
, wherein each occurrence of R, RL2B, RL2C and RL2D is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
-, [02071 cxlvii) L2 is NRL2A-, -NRL2AC(=O)-, -NRL2AC(=O)NRL2B
NRL2AC(=O)NRL2BCRL2cRL2D or -CRL2cRL2DC(=O)NRL2B, wherein each occurrence of RL2A' RL2s, RL2C and RL2D is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
[0208] cxlviii) L2 is NH-, -NHC(=O)-, -NHC(=O)O-, -NHC(=0)NH-, -CH2-C(=O)NH- or NHC(=O)NHCH2-;
[0209] cl) L2 is -NH-;
[0210] cli) L2 is -NHC(=0)NH-;
[02111 clii) L2 is -CH2-C(=0)NH-;
102121 cliii) L2 is NHC(=0)NHCH2-;
[0213] cliv) Z is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl moiety;
[0214] clv) Z is a branched alkyl, alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety;
[0215] clvi) Z is one of:

Rz~ Rz~
Rzl Rzl - V
ORz' N I{ N, Rz' N,Rzl wherein each occurrence of RZ1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl;
[0216] clvii) Z is a cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl moiety;
[0217] clviii) Z is cycloalkyl, cycloalkenyl, or a heterocyclyl, aryl or heteroaryl moiety having one of the structures:

z1 1 H
tR )m j ~ or ~ a wherein the "A" cyclic moiety is a 6- to 10-membered mono- or fused bicyclic aromatic ring comprising from 0-4 nitrogen atoms; the "Het" moiety represents a fully or partially saturated or unsaturated 5- to 8-membered mono-or fused bicyclic ring comprising 1-4 heteroatoms selected from N. 0 and S; m is an integer from 0-6; and each occurrence of RZ1 is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl, -ORZ2, -SRz2, -N(RZ)2a -SO2N(Rz2)2, -SO2Rz4,-C(=O)N(Rz2 )2, halogen, -CN, -NO2, -C(=O)ORZ2, -N(Rz2)C(=O)Rz3 or -N(RZ2)SO2 RZ4; wherein each occcurrence of e2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl;
or any two occurrences of RZ2, taken together with the nitrogen atom to which they are attached (e.g., N(Rza)a), form a substituted or unsubstituted heterocyclic moiety;
and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of RZ1 may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring;
[0218] clix) Z is one of:

(RZ1) (RZ1)m (Rz1)m (Rz')m (RZ1)m m r\~ N
~ N~ N
~~ NJ O
N
(R7-1)m (Rz')m (Rz1)'" (Rz1)m (RZ1)m ~ ~ :
N
S J
N O
Rza Rz1 (Rz1)m (Rz')m (RZ1)m ( )m (RZ1)m ,; +~ N"
~ ~
1~ ~N~~ N N
N ~ ~ ~g~ N ,,, ;, I~ Rza Rz4 (RZ1)m z1 ~S'\. RZ1 (RZ1)m ' N (RZ1)m ' N ~R

N ~ sr , N
" N' Z4 ww ww RZ4 R
(Rz')m N rl--N RZ1 RZ1 ~.~ /RZ1 (Rz1)m ~ ~~ ~ cs\ t ' r I
NrN N~N N\S~N N~p~N p r z1 Z4 (R m ) (RZ1)m\ (Rz4)m R~ (Rz1)m N O
N ~,N., N
~, z1 /
~
p N ' '' r ~ (R )m ~Z4 RZ4N~S ~ R? p Rz4 p~
N-S=O
z1 (Rz1) ~/, N(RZ1) "-y (R )m /
N> (Rx1)m (Rz1)m Rz RZ4 RZ4 ~-C0 ~ ~ ~-~~ / I ~-CNN f ~ I N (Rz')m ' 3 x X
R 1/ (RZ1)m R 1 0 ( )m ( )m wherein m is an integer from 0 to 3; r is an integer from 1 to 4; X3 is N or CRZ1; each occurrence of Rz1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORZ2, -SRz2, -NRz2Rz3, -SO2NRzzRz3' -SO2RZ1, -C(=O)NRz2Rz3, halogen, -CN, -NO2, -C(=O)ORZ3, -N(Rz2)C(=O)RZ3, wherein each occcurrence of RZ2 and e3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and RZ4 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl;
[0219] clx) Z is one of:

(Rz')m (Rz)m (RZI) m Rzl - r\ \ - (N~ r\ N (RZ1)m { N~N
~ ,,. 'N ~r~- \ s J
Rz4 N (RZ1)m RZ~)m O
I.,A X3 N
(RZ1)m Rz\ RZ4 Rz4 N
"\ I ( (~Z1)m O N N all ~
N N N
Rzl RZ1 z~ ~
( ) m ()m (R )m O
;
[0220] clxi) Z is one of:

I I
Rzl \ ORZ1 ' N= Rzs \ Rz1 N'Rzs II fl /JRZ~ ~ N N
J ~~ L!"', N N s zz R RZ2 H zi I _ N 'Rzs ~N\Rzs Tx> Rzi ~ N Xa N0 \
Rzl Rza Rzl Rzti Rz4 RZ4 Rz~ \N Rzl )c_RZ1 '41~N -~z 'N Rzi N
HN N HN jjRZ1 o wherein X3 is N or CRzI; Rzl is hydrogen, halogen, lower alkyl, lower hydroxyalkyl or lower haloalkyl; RZ2 and RZ3 are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or RZa and RZ3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; and RZ4 is hydrogen or lower alkyl;
[0221] clxii) Z is one of:
Rz~ ORz1 RZ1 H
\ N N'R~ N\
I / I~ N// N Rzl ~,L / Hzl I4. ,~ N ~
RZ1 RZ2 H z~
\ N, Rzs Rz2 \ N R
{~N N,Rz3 N-p RZ2 Rzi I\ R RZ2 Xf, N.Rza ~I\ ~'f ~ N R'R~ ~ N. za ~ae~ \%~ ~N-R~ Rz2 RZ3 Rzs N.
Rz3 RzIa RZ2A _ JN RzlA HN X HN X N \ /
'~~N X ~'~ 'z~N

HN
Rz2A
Rz, RZ1A HN 0 P~/
wherein X3 is N or CRzI; Rzl is hydrogen, halogen, lower alkyl or lower haloalkyl; and RZZ and RZ3 are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or e2 and RZ3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; X is halogen, RZIA is hydrogen, halogen, -CN, lower alkyl, lower alkoxy, lower haloalkyl or -SO2RZ';

wherein RZ4 is lower alkyl; Rzls is hydrogen or halogen; and RZ2A is hydrogen or lower alkyl;
[0222] clxiii) Z is one of:

R~1 OCX3 R -Rz2 N\
\ N N~i N z1 Rzl ~. I / ~-N =S= R
RZ1 Rzz H RZIA
\ N, RZ3 RZa Jli ~
~ N N, RZ3 N_ Rzi R N
N .Rz2 ~ / ~ ( ~> N '?zL~ Rza zz N.Rzs wherein X is halogen; Rz1A is lower alkyl; Rzl is halogen, lower alkyl or lower haloalkyl; and RZ2 and RZ3 are independently lower alkyl, or RZ2 and Rz3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring;
[0223] clxiv) Z is one of:

Rz1 RZ1 Rzl N/~OH \ \ R Z4 N ~ ~// \\
NS~N
Rzl I ~""' H

N N z2 ~N. z3 RzI Rzl R

Rzl . _N ~~'~~ =~ ~ ~ \ ~
~p N_O ( ~'4 ~ N
N- N
Rzl p N
N ~ NJ
N~ ' N

Rzl Rz2A

r-R N RZ1 N ~z 'N Rzt ~ N N

Rz\N zt xj)_Rz1 wherein Rzl is Cl, F, methyl or CF3; R Z2 and RZ3 are each methyl or ethyl, or taken together with the nitrogen atom to which they are attached form a saturated or unsaturated pyrrolidinyl ring; RzzA is hydrogen, methyl or isopropyl; and RZ4 is hydrogen or cyano;
[02241 clxv) Z is one of:
Rz' Rz' \ ~Rz4 ~ Rzt Rzl V%;Vv H
~ N
N~~
~
N-''C
\ / Rzt HN \ / Rzt HN Rzl JNZ
~4-~\
N N wherein Rzl is Cl, F, methyl or CF3; and RZ4 is hydrogen or cyano;

102251 clxvi) -L2-Z together represent a moiety having one of the following structures:

O O O
~~ '' J l ~~. N ~,N
N N~ z7 N " -~ 2 H ~J
H R H = '~ HN3 HN.XJ HN~-J3 --j 0 Rz2 0 Rzl 1-~-H~H.N,Rza N~Rzl H ORza wherein s is 0 or 1; X is -C(RZI)2, -C(=0)- or -SO2-; Jl, Jz and j3 are independently N, S, 0, NRZl or CRZl; each occurrence of RZl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORZZ, -SRZZ, -NR.z2Rz3, -SO2NRz2Rz3' -SO2RZ1, -C(=O)NRz2Rz3, halogen, -CN, -NO2, -C(=O)ORZ3, -N(Rz2)C(=O)Rz3, wherein each occcurrence of Rz2 and Rz3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and Rz3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring;
[0226] clxvii) -La-Z together represent -CH2-Cy or -NH-Cy where Cy is an optionally substituted bicyclic heterocycle;
[0227] clxviii) -L2-Z together represent a moiety having one of the following structures:
/-~-~~(RZ1)m ~(RZ1)m ~(RZi)m ~~(RZ1)m ( r,~ ( et H~--~ H et /--Het ~/-Het N-Het NT'Het wherein the "A" cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each "Het" moiety independently represents a fully or partially saturated or unsaturated 5- to 6-membered ring comprising 1-4 heteroatoms selected from N, 0 and S; m is an integer from 0-6; and each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -ORZ2, _SRZ2, -N(Rz2)2, -SOaN(Rza za za )Z, -S02R ,-C(=0)N(R )2, halogen, -CN, -NO2, -C(=O)ORZ2, -N(Rz2)C(=O)Rz3 or N(Rz2)SO2Rz4; wherein each occcurrence of RZ2 and Rz3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of Rz2, taken together with the nitrogen atom to which they are attached (e.g., N(RZ2)2), form a substituted or unsubstituted heterocyclic moiety; and RZ4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of Rz1 may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring;
[0228] clxix) -L2-Z together represent a moiety having one of the following structures:
(Rz1)m (RZ1)m H ~
He& N-Het wherein the "A" cyclic moiety is a 6-membered aromatic ring comprising from 0-4 nitrogen atoms; each "Het" moiety independently represents a fully or partially saturated or unsaturated 5- to 6-membered ring comprising 1-4 heteroatoms selected from N, 0 and S; m is an integer from 0-6; and each occurrence of Rz1 is independently hydrogen, lower alkyl, lower alkoxy, -SO2Rz4, halogen or -CN;
wherein RZ4 is lower alkyl;
[02291 clxx) -L2-Z together represent a moiety having one of the following structures:

aN ~(Rzi)m R N~l(Rz1)m R~ j(Rz1)m R~ N~i(Rz1)m ~~N H H N

0 \
Rz j(Rz1)m I(RZl)m N (Rzt)m Rz N (Rz1)m H

wherein m is an integer from 0-4; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -ORZ2, -SRZ2, -N(RZ2)2, -SO2N(RZ2)2, -SO2RZ',-C(-O)N(RZ2)2, halogen, -CN, -NO2, -C_Q ORZ2 z2 Z3 Z2 z4 Z2 , N(R )C(=O)R or N(R )SQ2R ; wherein each occcurrence of R
is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and wherein any two adjacent occurrence ofRZt may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring;
[0230] clxxi) -L2-Z together represent a moiety having one of the following structures:
Rzi Rz2 ~ RZ2 HN \ / Rzl N \ / Rz1 N Rz1 ~v \N H" Rzi HN

N_ HN
Zm Rz1 ~N NH H Q

wherein Rz2 is hydrogen or lower alkyl; each occurrence of RZI is independently hydrogen, halogen, -CN, lower alkyl, lower alkoxy, lower haloalkyl or -SO2RZ4; wherein RZ4 is lower alkyl;

[0231] clxxii) -L2-Z together represent a moiety having one of the following structures:
RZi A
-- ' Rz RZ1 = , ' \ ~ Rz1 = ~ ~ \ / R21 N\ Q
H N Rzi H H N

Rz~ --- HN ' Rzt ~ ~~
' HN
N Rzl ~\N1' ~,r~N~N
HN H/\'N H 0 wherein X is halogen, RZIA is hydrogen, halogen, -CN, lower alkyl, lower alkoxy, lower haloalkyl or -SO2Rz4; wherein RZ4 is lower alkyl; and Rza is hydrogen or lower alkyl;
[0232] clxxiii) -L2-Z together represent a moiety having one of the following structures:
Rzt -- - - RZ2 HN Rza 7~N Rzl HN Rzl N

N HRzi A H" 'N H~

N~ ~ H N -' N Rz~ ~
/N H \ N N
.

H
~
wherein RZ1 is Cl, F, methyl or CF3; and RZ2 is hydrogen, methyl or isopropyl; and/or [0233] clxxiv) -L2-Z together represent a moiety having one of the following structures:

N-HN \ / Rzi 7~N Rzt ~ Rz1 N Rzl H "N Rz, H '~ H '~''H~N

wherein Rzl is CI, F, methyl or CF3.
[0234] It will be appreciated that for each of the classes and subclasses described above and herein, any one or more occurrences of aliphatic or heteroaliphatic may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated and any one or more occurrences of aryl, heteroaryl, cycloaliphatic, cycloheteroaliphatic may be substituted or unsubstituted.
[02351 The reader will also appreciate that any and all possible combinations of the variables described in i)- through clxxiv) above (e.g., R2, L', L2, X', X2, Y and Z, among others) are considered part of the invention. Thus, the invention encompasses any and all compounds of formula I generated by taking any possible permutation of variables R2, L1, L2, Xi, X2, Y and Z, and other variables/substituents 1 3 X1A X2A x1B X2B Y1 Zl 2 1 2 (e.g.,R,R,R ,R ,R ,R ,R ,R etc.)asfurtherdefinedforR,L,L, Xl, X2, Y and Z, described in i)- through lii) above.
[0236] For example, an exemplary combination of variables described in i)-through clxxiv) above includes those compounds of Formula I wherein:
R 2 is hydrogen, halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
R4 is hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
X1A is NRI or -C(RXl)-; wherein R' taken together with a moiety present on L1 may form an optionally substituted heterocyclic ring;
X2A lS NR3 or -C(RXl)-; wherein one of X1A and XaA is -C(RXl)-, but not both;
XlB and X2B are -N- or -C(RXl)-; whereby one of XIa and XZB is -C(Rxl)-, but not both;
wherein R' and R3 are independently hydrogen, a nitrogen protecting group, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety; and Rx1 is hydrogen, halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
L1 is -W1-Alkl-; wherein Wl is 0 or NRWI, where RW1 is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alkl is a substituted or unsubstituted C 1.6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -C02-, -C(=O)C(=O)-, -C(=O)NRL1A_' _OC(=O)-, -OC( O)NRLIA_~ _NRL1AiqRL1B_, _ NRLIANRLIBC(=O)-, -NRLIAC(=O)-, -NRLIACO2-, -NRLIAC(=O)NRLIB_' _S(=O)_, -SO2-, -NRLIASO2-, -SO2NRLIA_, _NkLIASO2NRLIB-, -0-, -S-, or -NRL1A_; wherein each occurrence of RLIA and RLIB is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
L 2 is -C(=O)NRL2A_, _OC(=O)NRL2A_' _TqRL2ANRL2B_' _NRL2ANRL2BC(=O)_, -NRL2AC(=O)-, -NRL2ACO2-, -NRL2AC(=O)NRL2B_' _N]~L2ASO2-, _SO2NRL2A_' _ NRL2ASO2NRL2B-, or a substituted or unsubstituted CI-6alkylene or C2_6alkenylene chain interrupted with at least one nitrogen atom wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=O)-, -C(=O)NRL2A_, -OC(=O)-, -OC(=O)NRL2A_, _NRL2ANRL2B_, _ NRL2ANRL2BC(=O)-, -NRL2AC(=O)_, _NRL2ACO2-, -NRL2AC(=O)NRL2B_' _S(=O)-, _ SO2-, -NRL2ASO2-, -SO2NRL2A_, -NRL2ASO2NRL2B_, -0-, -S-, or -NRL2A_; wherein each occurrence of RL2A and R L2B is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl;
Y is a saturated or unsaturated cyclic ring system optionally- comprising one or more heteroatoms selected from S, N and 0;
Z is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl moiety.
[0237] Other exemplary combinations are illustrated by compounds of the following subgroups I through XVI:
[0238] I. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):
Wl,.AIkl.Y,L2 Z
R' wI,-AIk1.Y,L~z /l\ N N

N N N/N N
, J

(SP 1) (SP 2) Wi~AIkl,YL~Z W1~AIk1.Y,.L~Z
~N ~N
R4'N ~ J R4-N, J
or N N
(SP 3) (SP 4) wherein R', R3, R4, L2, Y and Z are as defined generally and in classes and subclasses herein; Wl is 0 or NRWI, where RWI is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and A1k1 is a substituted or unsubstituted C1.6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=0)-, -C(=O)NRLIA-, -OC(=0)-, -OC(=0)NRL1A-, NR L1ANRL1B-, -L1ANR LIB L1A L1AC02-, -NRL1AC(=0)NRL1B
NR C(=0)-, NRC(=0)-, -NR -, -S(=0)-, -SO2-, -NRLIASOa-, -SO2NRLIA-, -NRL1ASO2NRL1B-, -0-, -S-, or -NRLIA-; wherein each occurrence of RLIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl..
[0239] In certain embodiments, compounds of the invention have one of the structures (SP IA) through (SP 4A) below:

C1_salkyl~ Y Z
R~ NH e1 salkyl\ :L~ NH

N Y z NN f J
J I N
N~ R3 (SP IA) (SP 2A) C1-6alkyl\ L~ NH~~ salkyk~ ~,L~Z

- R
N ~ J 4-N, .- J
N or N
(SP 3A) (SP 4A) wherein the C1.6alkyl moiety may be substituted or unsubstituted.
[0240] In certain embodiments, compounds of the invention have one of the structures (1B) through (4) below:

~ I-salkyl\ ,L~
R' O~.C~-safkyl L' G Y z Y~ Z N
N N N,N N
N~ ( J ~
N 3 , R

(SP 1B) (SP 2 B) G~,Cl_salkyl L2 OCl-salkylYL\
Y z z e-N N R4-J R4_Nor N N

(SP 3B) (SP 4) wherein the CJ_6alkyl moiety may be substituted or unsubstituted.
[02411 In certain embodiments, for compounds of formulae (1A)-(4A) and (1r')-(4), the C1_6alkyl moiety is a substituted or unsubstituted C2alkyl moiety. In certain exemplary embodiments, the C1-6alkyl moiety is -CH2CH2-.
[0242] II. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

0 ~iY~ Rw2 z I Ll i~'~ N AG2 ~ Z L N. G2.
R N Rw2 N i A N
IV =N
3 N~
N R
(SP 5) (SP 6) Ll'-Y~Nk '- G2 z LNAG2 Z
N_ \ Rw2 Rwz R4-N ~ J R4-N.
N or N N ;
(SP 7) (SP 8) wherein R', R3, R4, L', Y and Z are as defined generally and in classes and subclasses herein; G2 is absent, 0 or NRGZ; and RW2 and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.

[0243] In certain embodiments, -N(RW2)C(=O)GZ- is NHC(=O)-, -NHC(=0)O-, or NHC(=O)NH-. In certain embodiments, compounds of the invention have one of the structures (SP 5A) -(SP 8") below:

p L1N~N~ Z
R' Li/YH
\NAH/Z H H
NN N N I J
I N

(SP 5A) (SP 6") Ll 1-Y-1 NAN~'Z Ll ~-Y\NAN
H H H H
,N1 N -N
R4'N ,,~ R4-N~ J
N or N N
(SP 7A) (SP 8A) [0244] III. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

LlY N'Z
i R~ L RNW2 RNw2 / N RW3 Rwa RW2 N N N~ J
N~ N3 N
N R
(SP 9) (SP 10) L~~Y'=NA Y
N z Ll~ N~Z
N' \ N RW2 Rw2 N Rw3 Rw4 Rwz R4'N /. I R4-N, or N N (SP 11) (SP 12) wherein R', R3, R4, L', Y and Z are as defined generally and in classes and subclasses herein; and RW2, RW3 and RW4 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
[0245] In certain embodiments, compounds of the invention have one of the structures (SP 9A) - (SP 12A ) below:

0 L --Y---~N_-IZ
Rl H
H H
N
N N N L, N' I ~ N N
N , R 3 (SP 9A) (SP 10A) L"-Y~N"kN~--~Z Ll --Y---~ N
H H H
N
R4-N ~- J R4-N, N or N N
(SP 11A) (SP 12A) [0246] IV. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

2 ~ ~2'J1 j'J L2 Ll i ~7 z RI Ll J,'~'~ Z ; (RY1)q N N (RY1)cj N N% R

(SP 13) (SP 14) j2-Jl L1 J,\Z Ll Z
N~ \ N (RY1)q N (RY1)4 N/ or N
(SP 15) (SP 16) wherein q is an integer from 0-2; R', R3, R4, L', L2 and Z are as defined generally and in classes and subclasses herein; and Ji, J2 and J3 are independently 0, S, N, NRYl or CRvl; wherein each occurrence of RYl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORY3, -SRY3, -NRY2RY3, -S02NRY203, -C(=O)NRv2RY3, halogen, -CN, -NOz, -C(=O)ORY3, -N(RY)C(=O)RY3, wherein each occcurrence of RY2 and e3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RYa and Rv3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.

[0247] In certain embodiments, compounds of the invention have one of the structures (SP 13A) - (SP 16A) below:
RY~l ! N L2 RYl N L2 '~ 'y z z L,///"'__,s R L~

N N Na/A N
N\ I J N N

(SP 13A) (SP 14A) RYl I NL2 RYl NL2 z z L~ S Ll S

N
N
R4-R4_N- ~' e--N or N N
(SP 15A) (SP 16A) [0248] In certain embodiments, compounds of the invention have one of the structures (SP 13A) - (SP 16A2 ) below:

R N 14 NL'Z
NA NiL~z Li 1 Li RY1 I
N ~N NjN
N
, I ~ N NJ

(SP 13A) (SP 14A) Rl 1 RY1 N-1~ N~L~z N='\N, L~z Ll \ LI \

N
4-N R4-N~
N or N N
(SP 15A) (SP 16A) 102491 V. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

(RY1)q J\
(RY1)q\.J' L

1 L1 ~ L~ Z L J\~ J Z
R \Js ~ N
N ( ~N N N I ~
N~ J N

(SP 17) (SP 18) (RY1)q 4 (RY1) q ' 4 J

L1 ~JsJ L~Z L1 -,Js L--Z

N~ ~N N
R4-N ~ R4-N\
N or N
(SP 19) (SP 20) wherein q is an integer from 0-3; R1, R3, R4, L1, L2 and Z are as defined generally and in classes and subclasses herein; and J4, J5 and J6 are independently N
or CRY ; wherein each occurrence of RYl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORY3, -SRY3, -NkY2RY3, -SO2NRY2RY3, -C(=O)NRv2RY3, halogen, -CN, -NO2, -C(=O)ORY3, -N(RYZ)C(=O)RY3, wherein each occcurrence of RYa and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.
[02501 In certain embodiments, compounds of the invention have one of the structures (SP 17A) - (SP 20A) below:
(RY1) (RY1) q JL ", Z q\ L2, z \

N N NN --~ i N

(SP 17A) (SP 18A) (RY1) q (RYl) q z ~~ ~ \ ~-11 Z
N~ N
R4-N ~ R4-N~ '~
N or N Ni (SP 19A) (SP 20") 102511 In certain embodiments, compounds of the invention have one of the structures (SP 17g) - (SP 20B) below:
(RY1)q 2 Y1 ~ L
(R )N~ \ L~Z N Z

R~ L1 --NN N /
N I J

N R
(SP 17B) (SP 18 B) (RY1)q Z (RY1)q 2 N Z

R4-N R4-N, or N N
(SP 19) (SP 20B) [02521 VI. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):
J1 W1 .-AIk1 j2_' J\ L2 R .-Alk1 ~ 2 \ L\Z Z

N I N (RY1)q N ~ I ( )q N N=J
'3 N R
(SP 21) (SP 22) W1,-AIk j2' J1 L W1--A1k1,~ Z-J 1 L~
z J~ Z
~ N RY1 Ra-~N~ N
N (RY1)q R4-N.N/ ( )q = N ~
(SP 23) (SP 24) j4 ERY1~q j4 (RY1)4 ,~AIk ~ ?

1 ~ YL2 W1.~AIk1x~ 2 j5 Z

N j~js~ L,~Z N/ i iN ~js N ( J N NJ

N R ;
(SP 25) (SP 26) j4 (RY1)q j4 (RY1)q 1~AIk1 r! ~~ 2 i~Afk1~ ~j 2 W J ') L"Z J5 L~Z
W
N., ~ N js .' N -= js R4-N ~- J R4-N. ~ J
N or N N ;
(SP 27) (SP 28) wherein R', R3, R4, L 2 and Z are as defined generally and in classes and subclasses herein; WI is 0 or NRW1, where RWI is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk, is a substituted or unsubstituted C1_6alkylene or Cz_balkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -COa-, -C(=0)C(=0)-, -C(=O)NRLIA-, -OC(=O)-, -OC(=O)NRL1A-, NRLIANRLIB
-, -NRLIANRLIBC(=O)-> -NRLIAC(-0)-> -NRLIACO2-, -NRLIAC(_O)NRLIB
-, -S(=0)-, -SO2-, -NRLInSO2-, -SO2NRLIA-, NRLInSOaNRLIB-, -O-, -S-, or -NRLIn -; wherein each occurrence of R LIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3;
Jl, J2 and J3 are independently 0, S, N, Ne1 or CRY'; J4, JS and J6 are independently N
or CRYl; wherein each occurrence of RYI is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORY3, -SRY3, NRYaRY3, -SO2NRY2RY3, -C(=0)NRY2RY3, halogen, -CN, NOZ, -C(=O)OR}'3, -N(RYZ)C(=O)RY3, wherein each occcurrence of RYZ and e3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RYZ and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.
[0253) In certain embodiments, in compounds of the formulae (SP 21) -(SP 24) the 5-membered ring having the structure:

,~'j2-J~ ~

J~
(RY1 )q;
has one of the following structures:

RY1 N N %~N>' i' ~~-~'RY

[0254] In certain embodiments, in compounds of the formulae (SP 25) -(SP 28) the 6-membered ring having the structure:
J4 (RY1)q ~ e J, Js~
has one of the following structures:

(RY1 )q (RY1 ~q [0255] In certain embodiments, -W1-A1kl- is NHC1_6alkyl- or -OC1_6alkyl-. In certain embodiments, -W1-AIkt- is -NHC2alkyl- or -OC2alkyl-. In certain embodiments, -Wi-Alkl- is -NHCH2CH2-, -OCH2CH2- or NH-CHzCH(CHzOH)-.
[0256] VII. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

(RY1)q (R )q RW2 RW2 N G2, J2. J? N G2 L1 z RI L1 J~ ~ 'Z 0 ~N ~ N 0 N /
N\ I J N N

N
(SP 29) (SP 30) (RY1)q RW2 CRY1,q RW2 J2. -J1 N G J2 -J1 i Ll 2,Z Li J N If G2, Z
O O
N- N N
R4'N ~ J R4-N. - J
N N N

(SP 31) (SP 32) (RY1)q j4 (RY1)q 4 W2 Ay5 JR ~ N G2~z R1 L 1 J gJ N''Gz~Z J~O

e\. N O N/ N3 N
N R
(SP 33) (SP 34) (RY1)q Ja Rw2 (RY1)q ,~4 Rw2 A-.- ~\r Ll.J6"1 N-f G2, Z ~-l ~5 js-) NyG2,Z N G ,., 'N

R4-N R4"N Q
.N. NJ
or (SP 35) (SP 36) wherein R1, R3, R4, Lj and Z are as defined generally and in classes and subclasses herein; q is an integer from 0-3; Jl, J2 and J3 are independently 0, S, N, NRYI or CRY'; J4, J'and J6 are independently N or CRY'; wherein each occurrence of RYl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORY3' -SRY3, -NRY2RY3, -SazNRY2RY3, -c(=a)NRY2RY3, halogen, -CN, -NOz, -C(-O)ORY3, -N(RY)C(=O)Rv3, wherein each occcurrence of RY2 and R~3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; G2 is absent, 0 or NR.GZ; and RW2 and RGZ are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
[02571 In certain embodiments, in compounds of formulae (SP 29) -(SP 32) the 5-membered ring having the structure:
~1-jz_j' ~
(RY1)Q;

has one of the following structures:

N
RY1 N , N %\
~ ~y ~
S \ Y1 (0258] In certain embodiments, in compounds of formulae (SP 33) - (SP 36) the 6-membered ring having the structure:
J4 (RY1)q J5,~
, has one of the following structures:
(RY1 )q (RYI ~q =~

[0259] In certain embodiments, -N(RWZ)C(=0)Ga- is NHC(=O)-, -NHC(=0)O-, or NHC(=0)NH-.
10260] VIII. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

(RY1)q O RW3 RW4 (RY1iq W3 W4 ~ z _J1 I

J' N N Z N\
R1 L1 -ji Rw2 Aw2 R1 L1 Z
O
N ~N N N
N~ I J NI
N N
(SP 37A) (SP 38A) OY1)q 0 RWS RW4 (RY1)q Rw3 RW4 RW2 Jz -j1 -J~ (v N Z j2' -J\ N
L1 RW2 RWZ L \Z
O
N~ N N N

N N ;
(SP 39A) (SP 40") (RY1)q ~ RW3 Rw4 (RY1)q RW3 RW4 RW2 _ 1 I
% ~J1 N~N Z ~ N~
Ll ~~ RW2 Rwz L1 j~ Z
Q

N N N N
N, N N/ ~

R3 i R3 ' (SP 37B) (SP 38B) (RY1)q O RW3 RW4 (RY1)q RW3 RW4 RW2 J2 "~1 NNZ Jz. _i~
L1 ~~ RW2 Rw2 L1 j Z
O
N
R4-N N NRa_NN " . ~ :~N

(SP 39B) (SP 40B) (Ryl)q 4 0 RW3 RW4 (Ryl)q j4 RW3 RW4 W2 ~\J1 J~ =~ ~\ ~ N
N N ~ 1 L1~~ 6J ~Z
R1 L1~~Js~ Rw2 Rw2 i O
N N N I N
~
~
N NJ
(SP41''') (SP 42A) (Ryl)q ' ~ RwRwa (RY1) ~\JRW3 Rwa RW2 L1 a\ ~ NwRw2 L1~~J6J N\Z
N O

J R e-N

R N

(SP 43A) (SP 44A) (RY1)q 4 Q RW3 RW4 (Ryl)q j4 RW3 RW4 W2 J~ r\ R
AN Z N
L1~~Js~ Rwz Rwz L1 J5 ",js) O Z
N N/ I I
N=N N N 3 N

(SP 41B) (SP 42B) (RY1)q y Rwa RW4 iRY1)q J4 Rw3 RW4 RW2 r~ 1 \1 NNZ l1i5 N
Jjfi~ Rw2 RW2 6~ 2 O
R4-N1 ~ J R~-N' ~ !J
N N or N N
(SP 43B) (SP 44B) wherein R1, L1 and Z are as defined generally and in classes and subclasses herein; q is an integer from 0-3; J1, J2 and J3 are independently 0, S, N, NRYI or CR" ; J4, J5 and J6 are independently N or CRY'; wherein each occurrence of RY1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)hetervaryl, -ORY3, -SRY3, -NRY2RY3, -SO2NRY2RY3' _C(=O)NRv2RY3, halogen, -CN, NO2, -C(=O)ORY3, -N(RY2)C(=O)RY3, wherein each occcurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; RW3 and R" are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; and RW2 is hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
10261J In certain embodiments, in compounds of formulae (SP 37A"a) through (SP 40A-B) the 5-membered ring having the structure:

j 2~J' (RY1)q}
has one of the following structures:

RYi N N %4 ~Y- N
S ~C" ~
RYi (02621 In certain embodiments, in compounds of formulae (SP 41A'B) through (SP 44A'B) the 6-membered ring having the structure:
J4 (RY1)q yl J5Js~
has one of the following structures:

(RY1 )q (RY1 ~q -N ~

[02631 In certain embodiments, -N(RW2)C(=O)N(RWZ)CRW3RW4- is -NHC(=O)NHCHa-, and -CRW3RW4C(=O)N(RW2) - is -CHZC(=0)NH-.
[0264] IX. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

t)q RW2 (Ryl)q RY1 RW2 AIk, J2. -J~ i Alkl J2 -J\ Wl i ~ NG2.
R~ W1 J~ NG2~Z \ J~ IOI Z
N N O N, ( N
N N NJ

N ; R ;
(SP 45) (SP 46) (Ryl)q 1 RW2 (Ryl)q RW2 W1~AIkl J2..J N G2' AIk, 4Jr- ' J,II z W1 N 'Y G2'z N O N O
R4-N Ra-N, N or N N
(SP 47) (SP 48) wherein Rl, R3, Ra and Z are as defined generally and in classes and subclasses herein; W' is 0 or NRYI, where RWl is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alkl is a substituted or unsubstituted C1_6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -C02-, -C(=O)C(=O)-, -C(=O)NRL1A-, -OC(=0)-, -OC(=O)NRLIA-, -NRLIANRLIB-, -NRL1ANRLIBC(_O)-, -NRLIAC('O)-, 'NRL1AC02-, -NRL1AC(_O)NRLIB
-, -S(=O)-, -SO2-, -NRLIASO2-, -SO2NRLIA-, -NRL1ASO2NRLIB-, -0-, -S-, or -NRL1A-; wherein each occurrence of RLIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3;
J 1, J2 and J3 are independently 0, S, N, NRYI or CRY'; wherein each occurrence of RYl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORv3, -SRY3, NRY2RY3, -SO2NRY2RY3, -C(=O)NRYZRY3, halogen, -CN, NO2, -C(=0)ORY3, N(RY2)C(=O)RY3, wherein each occcurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, atyl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RYZ and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; G2 is absent, 0 or NRG2; and Rr and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
(0265) In certain embodiments, compounds of this class have the structure (SP
45A-B), (SP 46A-11), (SP 47"-11) or (SP 48A-8) below:
tRY1)q (Ryl)q C1-6alky~ 2 _ 1 RW2 C -6alkyl = -J1 RW2 G J ~
HN ~ ' N~G2, Z' j HN/~ j ~ z ~
N N j O Z N~ ~ N O
N~ I J iV N

(SP 45A) (SP 46A) Y1 (RY1)q j~ salkyl 32qRW2 j1 6alkyl ~2 ~~1 NWZ G
HN NGz, HN ~
y Z Z
N Z, j O ~ G
1 ~ ~ N
R4-N N R4'N. . ~
N N N
(SP 47A) (SP 48A) Y1 (Ryl)q ~R ~q RW2 ~1-6alkyt JZ= - J1 Rw2 ~1 0 %1-6alkyl J2 i O ! NGz~
N G2, j y Z
N 'N j O
~ Z N~ ! N 0 , NJ
N \ NJ or R3 (SP 45B) (SP 46B) (Ryl)q (Ryl)q C1-6alkyl Rw2 C1-6alkyl ~ {~w2 o' j Nu 'I G21 Z O/ i 2= -J NG2' Z
3~
~N 0 N
Ra-N ~ R4-N, J
N or N N
(SP 47B) (SP 48B) wherein the C1-6alkyl moiety may be substituted or unsubstituted.

102661 In certain embodiments, for compounds of formulae (SP 45)-( SP 48), -Wi-A1k1- is-NHC2alkyl- or -OC2alkyl-. In certain embodiments, -Wl-Alkl- is -NHCH2CH2-, -OCH2CH2- or NH-CHZCH(CHZOH)-.
102671 In certain embodiments, for compounds of formulae (SP 45A'$)-( SP 48A"
B) the C1_6alkyl moiety is a substituted or unsubstituted C2alkyl moiety. In certain exemplary embodiments, the C1_6alkyl moiety is -CH2CH2-.
[0268] In certain embodiments, in compounds of formulae (SP 45)-( SP 48), and (SP 45A"11)-( SP 48A"B) the 5-membered ring having the structure:

j ,~1j2-J;

(RY1) a, has one of the following structures:

RY7 N N %\N~\' ~zL l S Y1 In certain embodiments, -N(R.Wa)C(-O)G2- is NHC(=0)-, NHC(=O)O-, or NHC(=0)NH-.
[0269] X. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

RY1 (Ryl)q O R W3 RW4 ( )q O Rws Rwa Alk, Jz _J~

~Alk~ 4JIJ- W ~~ N~N Z
Wl N~NZ Rwz Rw2 RWZ Rwz N/ I N
N ~N J
~ N

(SP 49A) (SP 50A) (Ryl)q 0 Rw3 RW4 (Ryl)q 0 :-W2 w3 W4 Rw2 N Rwz R4-N 1~4-N
N N~
N
(SP 51A) (SP 52~) Y1 (RY1)q RW3 ~R ~a ws Rwa Rw2 R Rwa w2 1A{kl j2. - J, I
R1 W1~ AIk1 J2. J N W ~ N,'Z
.N ~ N J p'Z N/ ~ J N p N~ ~ N3 N
N R
(SP 49B) (SP SO8) (RY1~9 (RY1)q ~ Alkl Jz. _ Jh RW3 RWa Rw2~ ~Aik, W3 ~~w2 R
' ~ JN~Z W ~ Z
~ 4JIJ-~-Y
N'- N O ~N O
Ra-N Ra-N, J
N N
(SP 51$) (SP 52B) wherein R1, R3, R4 and Z are as defined generally and in classes and subclasses herein; W' is 0 or NRWI, where RWl is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; A1ki is a substituted or unsubstituted C1_6alkylene or C2.6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02,-, -C(=O)C(=O)-, -C(=O)NRL1A-, _OC(=O)-, -OC(=O)NRL1A-, NRLIANRLIB
-, -NRLIANRLIBC(-O)-, -NRL1A',(!O)_, -NRLIAC02-, -NRL1ACr=O)~LIB-, -Sr O)-, -SOa-, -NRLIASO2-, -SO2NRLIA_, _NRLIASO2~LiB_, -0-, -Sl-, or -NRL1A-; lwherein each occurrence of RLIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3;
JI, J2 and J3 are independently 0, S, N, NRXI or CRY ; wherein each occurrence of RYI is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(a1ky1)heteroaryl, -ORY3, -SRY3, NRY2RY3, -SOZNRY2RY3, -C(=O)NRY2RY3, halogen, -CN, -NO2, -C(=O)ORY3, -N(R.X2)C(=O)RY3, wherein each occcurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RYZ and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; R" and RW4 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; and Rw2 is hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.

[02701 In certain embodiments, -W'-Alkl- is -NHC1_6alkyl- or -OC1_6alkyl-. In certain embodiments, -Wl-A1ki- is =NHC2alkyl- or -OC2alkyl-. In certain embodiments, -W' -AIkj - is -NHCH2CH2-, -OCH2CH2- or NH-CH2CH(CH2OH)-.
[0271] - In certain embodiments, in compounds of the formulae (SP 49"-B) through (SP 52A"B), the 5-membered ring having the structure:
jZ--J' J
(RY1)q;
has one of the following structures:

RY1 N '~. N-~N~~
~'~
S \/RYi [0272] In certain embodiments, -N(RW2)C(=O)N(RW2)CRW3RWI- is -NHC(-0)NHCHZ-, and -CRwsRwaC(=O)N(RW2) - is -CHzC(=O)NH-.
[0273) XI. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

(Ryl)q d W2 (R1Y1 1Q r Ja RW2 ~ i G
N ~ 2-z 1 r\J N G2 W1 Alk J~J6~
Alk ;, -R1 Wl J'J6J ~ _Z t N p N i N

N I J

N R ;
(SP 53) (SP 54) ( )q J
A 4 RWZ ~ >q J4 ~Wa ~ i A{k , W1 7 ~ Js NyO2~Z Aik1 ~ Js NyG2, z O O
e-N N R4R4-N. or N N

(SP 55) (SP 56) wherein Rl, R3, R4 and Z are as defined generally and in classes and subclasses herein; W' is 0 or NRWI, where R'vj is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; A1k1 is a substituted or unsubstituted C1.6alkylene or C2_6alkenyiene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -COz_, -C(=0)C(=0)-, -C(=O)NRL1A_) -OC(=0)-, -OC(=0)NRL]A-, -NRL1ANRLiB-, --~aLIA~L1Bc(~0)-, -NRLIAC(=O)-, _NRLiACQa,' -NRLIAC(_O)NRL1B-, -S(=0)-, _ S02-, -NRLIASQ2-, -SO2NkL1A-, -,~aL1AS42imLI13-, -0-, _S-, or -NRLIA-; wherein each occurrence of R~ IA and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3;
J4, JS and J6 are independently N or CIO; wherein each occurrence of Ry1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -Oe3, -SRP, -Nele3, -S02NRPjJ3, -C(-O)Ne2RY3, halogen, -CN, -NOa, -C(-O)ORYS, -N(e2)C(=O)RY3, wherein each occcurrence of R~2 and RX3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached fornl a 5-6 membered heterocyclic ring; GZ
is absent, 0 or NRGZ; and R W2 and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
[02741 In certain embodiments, the compounds have the following structures:
tRYt)a ~RY~~~ C1-salkyf\J\ ~W2 ~.6a1kY\J~ RW2 HN j5' I~I G2.
Rti HN Jg. NG2.,Z z ~N ~ N 0 N/ A J
N N
N ; R
(SP 53A) (SP 54A) W7 )q (RYti )q C1-6alkyi 'j4 RW2 Cj.6alkyl ~J4 RW2 HN~ ~ N G2~ HN 11 - N G2.
~.,6 y Z -.J6 y Z
N-.. -N 0 .~ ~ N 0 R4-N R4'N. ,.
N N
(SP 55A) (SP 56A) (RY1)a 1RY1iq C~~6alkyl~'.f\ RW2 ~.saikY\'J4 RW2 Q~ 5 Nu G2.
RI G j + 5 ) N ~ ' G 6 Z
N
-J6 Z N~ N 0 N~ I !J 0 N
N or Rs (SP 53a) (SP 54B) (RY1)q (RYl)q C1_6alkyl J4 RWZ C1_6alkyl J4 RW2 p~ 5 N G2~ OO 5 N GZ, J~Js~ ~ Z JJ6) ~ Z

R4-N R4-N/zz N or N N ;
(SP 55B) (SP 56B) wherein the CI,6alkyl moiety may be substituted or unsubstituted.
[02751 In certain embodiments, for compounds of formulae (SP 53)-( SP 56), -W1-Alkl- is-NHC2aIkyi- or -OC2alkyl-. In certain embodiments, -W'-Alkl- is -NHCH2CH2-, -OCH2CH2- or NH-CH2CH(CH2OH)-.
[0276] In certain embodiments, for compounds of formulae (SP 53A"a) through (SP 56A"B), the C1_6alkyl moiety is a substituted or unsubstituted C2alkyl moiety. In certain exemplary embodiments, the C1.6alkyl moiety is -CH2CH2-.
[0277] In certain embodiments, in compounds of the formulae (SP 53)-( SP 56) and (SP 53A-B) through (SP 56A"), the 6-membered ring having the structure:
J4 (Ry1)q J'J6-) has one of the following structures:
(Ryl)a\ (RYI)N\ k -'~, '.'',=. .

In certain embodiments, -N(RW2)C(=O)G2- is NHC(=0)-, NHC(=0)O-, or -NHC(=O)NH-.
[0278] XII. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):
Y1 Rwa RW4 (RY')q p Rws Rw4 IR )q \ C
4 V Aikl N~NZ
~Afkl NN~\Z W1~ J~Js~ Rw2 Rw2 W, J~'Js R~ ~~ ~

e\NN N/ J
R
(SP 57A) (SP 58A) (RY1) O RW3 RW4 (RY1)q 0 Rvus RW4 AIk1 ~\J~ N~N~z ~,Alk~ (~J ~ N-,~ N z Wi~ J~Js~ RW2 RW2 Wi J~Js" RW2 RW2 ~
N ~N
R4-N ~ N J ,Ra-N, ~ NJ
a (SP 59A) (SP 60A) (RY1) Rw3 (RY1)p \ RW3 R l RW4 N
q J4 RW4 W2 A!k ~ a ~
Alkl 5 N W~~ ~~Js'1 ~Z
Wl J"Je~ ~Z ~ 0 NfN N 0 N/
~ ~ N N
N ; R3 ;
(SP 57) (SP 58a) (RY1l ~ J4 ~,w3 Rwa W2 (RY1,q J4 RW3 RW4 W2 R ~
~ AIk~ ~\ j ~ Aik, r~ 1 N\
W1 1Js ~Z W1 J.Js'1 Z
N \N 0 ' ~N 0 4-N J R4-N, ) N or N
(SP 59B) - (SP 60B) wherein Rl, R3, R4 and Z are as defined generally and in classes and subclasses herein; Wl is 0 or NRWI, where R'Nl is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk, is a substituted or unsubstituted C1_6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=O)-, -C(=O)NRL1A_, -OC(=O)--, -OC(=O)NRL1A_b _NRLIANRLIB_, -NRLIANRLIBC(=O)-, NRLIAC(=O)-, NR~IACO2-, -NRLiAC(=O)NRLIS_' _S(=O)-, -SOa-, -NRLIASO2-, -SO2NRLtA', -NRL1ASO2NRL1B-' _O-, -S-, or NRL1A-; wherein each occurrence of R LIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3;
J4, JS and J6 are independently N or CRYI; wherein each occurrence of RYl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORY3, -SRY3, NRY2Ry3, -SO2NR'Y2e3, -C(=O)NRY2RY3, halogen, -CN, NOa, -C(=O)Oe3, N(RY2)C(=0)RY3, wherein each occcurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RYZ and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring;
RW3 and RW4 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; and RW2 is hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
[0279] In certain embodiments, -Wl-A1k1- is NHC1_6alkyl- or -OC1.6alkyl-. In certain embodiments, -WI-AIkI- is -NHC2alkyl- or -OC2alkyl-. In certain embodiments, -W1-A1k, - is NHCH2CHZ-, -OCH2CH2- or NH-CHaCH(CH2OH)-.
[0280] In certain embodiments, in compounds of the formulae (SP 57A-B) -(SP
60A"B) the 6-membered ring having the structure:
J4 (RY1)G
J--,j6, has one of the following structures:
(RYl}q\ (RYt~N~

[0281] In certain embodiments, -N(RW2)C(=O)G2- is NHC(=0)-, -NHC(=0)O-, or NHC(=O)NH-.
[0282] In certain embodiments, -N(Rw2)C(=O)N(RW2)CRw3Rw4_ is NHC(=O)NHCHZ-, and -CRW3RW4C(=O)N(RW) - is -CH2C(=O)NH-.

[0283] XIII. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):
AIk1 N H Wl~AIkj _ /~'~N N'Z
N N, O
R ~ W1 ~~ H
Z / N S
N N 0 N~

NN NJ R N

(SP 61A) (SP 62A) W1~Aik~~ ~ N N H W1~AIk1 ~ N N H
\S~ N-Z ~ N'Z
N ly 4_ lOl R4-N NJ R N' - NJ
N
(SP 63A) (SP 64") ~AIk~ N H ~,AIki N
Rxl Wi ~~N M1Ni. R1 WI ~~N N.
N~ N S ~ z NN N ~" z N NJ ', - NJ

~3 . RXi (SP 61") (SP 62$) JAIkl N H
A1k N N
H Wi Rx1 Wi ~N ~, z N' 'N S i'' Z
-N _.~ N Y R4_N f i O
R4,.,. ~ NJ
N N or Rxi (SP 63) (SP 64$) wherein RI, R3, R4 and Rxl are as defined generally and in classes and subclasses herein; Z is an aryl, heteroaryl or heterocyclic moiety; WI is 0 or NRWt, where RWI is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alkl is a substituted or unsubstituted C1_6alkylene or C2.
6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C{=O)-, -COz-, -C(=0)C(=O)-, -C(=O)NRLIA-, -OC(=0)-, -OC(= O)NRLIA-, -NftLlANkL1B-, _NRLIANRLIBC(=O)_s NRL]AC(=O)-, -NRLIACO2-, NRLIAC(VO)NRL1B-' -S(=O)-, -S02-, _NRLIAS02-, -S02NRLIA-, -NRLIASOzNRLIB
_' -0-, -S-, or -NRLIA-; wherein each occurrence of RLIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; and each occurrence of Rz1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkYI)heteroarY1, -ORzz, -SRza, =1VRz2Rz3, -SO2NRzaR.z3, -SUzRzi, -C(=0)NR
zzRz3 , halogen, -CN, -NOz, -C(=O)ORzs, -N(R2z)C(-O)RZ3, wherein each occcurrence of RP and Rz3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or e2 and Rz3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
10284j XIV. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

~A1k1 N H
R1 W1~AIk1-v ~/, ~N N W1 grNr ~ Rz1)m ' ~ ~
N j O
N S I~ (RZ1)m N/ I
O ' N N N

(SP 65A) (SP 66A) W1~_AIk1- ~, ~N N W1" AIk1~~N H
~
N1 ~ N ~ i~ tRZ1)m ~ ~ N S ~ I '(RZ1)m R4-N O / R4_N, O
N i N N
(SP 67A) (SP 68A) Rx1 W1"AIk1\CyN N R1 W1"AIk, ~, N
S ~
~ I ~ (Rz1)m N ~ ~ I ~ ~Rz1)m J o / N\ I N o N NJ
Rs Rx1 (SP 65) (SP 66B) AIk1 N H W1 AIk1~ I''N H
x1 W N
S ~ \ N' ~ N ~(Rz1)m Ri y N S ~
4 N o + ~ ~RZ1)m Rq_N O /
R - N,J N
N N or Rx1 (SP 67B) (SP 68n) wherein R', R3, R4 and R~'1 are as defined generally and in classes and subclasses herein; Wl is 0 or NRWI, where RW1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1_6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=O)-, -C(=O)NRLIA-, -OC(=O)-, -OC(=O)NRLIA-, -NRL1ANRLls-, _ NRLIANRL1aC(=0)-, -NRLiAC(=O)-1-NRL1AC02-, _NRLIAC(=O)NRL1B-, -S(=0)_, _ SOz-, -NRL1ASO2-, -SOZNRLIA-, -NRLIASOZNRLIB-, -0-, -S-, or -NRL1A-; wherein each occurrence of RL1A and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from I to 4; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORz2, -SRz2, -Ne2Rz3, -SO2NRz2Rz3, -SOZRz1, -C(=0)NRz2Rz3, halogen, -CN, -NO2, -C(=0)ORZ3, N(Rz2)C(=O)Rz3, wherein each occcurrence of RZZ and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
[0285] In certain embodiments, for compounds of groups XIII and XIV, -W'-Alkl- is NHC1_6alkyl- or -OC1_6alkyl-; wherein the Cl_6alkyl moiety may be substituted or unsubstituted. In certain embodiments, -W'-Alkl- is-NHC2alkyl-or -OC2alkyl-. In certain embodiments, -W1-A1ki- is -NHCH2CH2-, -OCH2CH2- or -NH-CH2CH(CH2OH)-.
[0286] In certain embodiments, for compounds of group XIV, Rz1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is 1 and RZl is halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is 1 and RZl is Cl, F, methyl or -CF3. In certain embodiments, m is 1 and RZl is lower haloalkyl. In certain embodiments, m is 1 and RZl is -CF3. In certain embodiments, m is 2 and each occurrence of RZl is independently CN, Cl, F, methyl or -CF3. In certain embodiments, m is 2 and each occurrence of RZl is CN, Cl, F, methyl or -CF3.
In certain embodiments, m is 2 and one occurrence of RZ1 is Cl, F, methyl or -CF3 and the other is CN.
[02871 In certain embodiments, compounds -of-group XIV have-the structure:
C2alkyl~~' N H H
Rzt z Wi C2alkyl \ yN H N R W,/ \SyN~'N C
N z~
Ri S '~ ~N O NN N ~ NN~
N ~ NJ
~J R3 (SP 65A) (SP 66A) C2alkyl N H C2alkyl N H H
Wt1' ~~N~N al~ Rzt Wi~ ~~N~N C Rzl N ; R4-N
N or N
(SP 67A') (SP 68") wherein Wl is NH or 0; the C2alkyl moiety is optionally substituted; Rl, R3 and R4 are independently hydrogen, lower alkyl or -CO2RIA where R IA is hydrogen or lower alkyl; RZl is halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, RZ' is Cl, F, methyl or -CF3. In certain exemplary embodiments, Rz' is Cl or -CF3. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[0288] In certain embodiments, compounds of group XIV have the structure:

,~ Zalkyl\ ~yN N Rzl CZalkyl ~ N H M W '~S CIIIICN
N~N N 'N O I J
N ~ CN N N

(SP 65~Z) (SP 66A) W,~ 2alkyl1 /; y~~~ \ RZ1 W,, C2aIky1~~NYN Rzl ~ ~
N~ N O / a,, N O
R4-~CN R4_N CN
N or N%
(SP 67A2) (SP 68A2) wherein Wl is NH or 0; the C2alkyl moiety is optionally substituted; R', R3 and Ra are independently hydrogen, lower alkyl or -C02R1A where R1A is hydrogen or lower alkyl; el is halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, el is Cl, F, methyl or -CF3. In certain exemplary embodiments, RZl is Cl or -CF3. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[0289] In certain embodiments, compounds of group XIV have the structure:
C aIky\ l\~ H 2 alkyl RxI 2 " NyN ' RZ1 R\ Wi ~ al' N ~ \ Rzl Ni N C I/ N N '" /
N ~ \r~
N NJ
\
R3 Rxl (SP 65B1) (SP 66B2) Czalkyl\~ N H H
i 2alkyl ~ N H H \S,r N~IV Rzt \
Rx~ Wi \S~N N \ RZ1 Ra- N '/
' \-J ~ I / N J
R4-N~J
N N or Rxl (SP 67B1) (SP 68BI) wherein W 1 is NH or 0; the C2alkyl moiety is optionally substituted; R', R3 and R4 are independently hydrogen, lower alkyl or -C02R1A where R1A is hydrogen or lower alkyl; RXi is hydrogen, lower alkyl or heterocyclyl; and Rzl is halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, el is hydrogen, methyl or thienyl; RZ1 is Cl, F, methyl or -CF3. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[0290] In certain embodiments, compounds of group XIV have the structure:

j zalkyl~ ~~'N H H C2alkyl N
Rxt Wi \S~-'N~( \'N Rz' R\ W1 ~~N N Rz1 S ~
N ~\N 0 I~ CN N ~N O
N NJ N\ CN
N
Rs ~ Rx9 ~

(SP 65B2) (SP 66B2) C2alkyl N H
Czalkyl N H W, x1 Wl/ N N RZ7 / gyN~'N I Rz~
R S a_ N- N 0 a_ N{ O~GN R N~ NJ
R NN NJ or Rx' (SP 67B) (SP 68BZ) wherein Wl is NH or 0; the C2alkyl moiety is optionally substituted; R1, R3 and R~ are independently hydrogen, lower alkyl or -CO2R1A where RIA is hydrogen or lower alkyl; Rxl is hydrogen, lower alkyl or heterocyclyl; and RZ1 is halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, Rx1 is hydrogen, methyl or thienyl; and RZ1 is Cl, F, methyl or -CF3. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[0291] XV. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

'~Alkt, N N N HN N H ~ Alkl N H HN W
Rt W1 syN N S ~ (~(Rz')m N \ N Y f~(Rza)m N~ ~ J O /
O
N
N
N~ =
, =
~ R3 (SP 69A) (SP 70") W'-,Atkj\ N H H HN-1 1-õAlkj N,1 H H HN-N N N W N N ~ N
N S Y ~-(Rz1)m , S a ~ j(Rz1)m R4-N~J O = R4'N. ~ .J
N N N ~
(SP 71A) (SP 72A) x1 Wl.~Alkti~ N H H HN-\\ 1i Ikj ~ N~~ "H H HN~
R uN N
N~/N N R? W /~ N
N~ I~N S IOl (RzI)m NN I~N IOI (_(RZ1)m N Nf N
R3 ~ Rx1 =
(SP 69B) (SP 70B) Rxl WAIki ~; N N ~ HN N W1~ Ik1 'S~NYN ~ N
Sy ~ N~ ~ ~ j(RZt)m R4-N ~ p ' ~ (RZ1)m Ra-N C Nf N N or Rxl (SP 71B) (SP 72) wherein Rl, R3, R4 and RXl are as defined generally and in classes and subclasses herein; Wl is 0 or NRW1, where RWl is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; A1k1 is a substituted or unsubstituted C1.6alkylene or C2.6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -CO2-, -C(=O)C(=O)-, -C(=O)NRL1A-, _OC(=O)-, -OC(=O)NRL1A_y _NRLIANRL(B_, _ -P~aL1ATqRLIBC(_O)-, -NRLIAC(=O)-, -NRL1AC02-, -NRLIAC(=O)NRL1B_, _S(~O)_, _ SO2-, NRLIASO2-, -SO2NRLIA-, NRLIASOZNRLIB-, -0-, -S-, or -NRL1A_; wherein each occurrence of RLIA and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of Rzl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORza, -SRZ2, -NRzzRz3' _SO2NRzaRz3, _SO2RZ1, -C(=O)NRz2Rz3, halogen, -CN, -NO2, -C(=0)ORZ3, -N(Rz2)C(=O)Rz3, wherein each occcurrence of Rz2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and Rz3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
[0292] In certain embodiments, for compounds of group XV, -W1-Alkl- is -NHC1.6alkyl.- or -OC1_6alkyl-. In certain embodiments, -Wl-Alkl- is-NHCzalkyl-or -OC2alkyl-. In certain embodiments, -Wl-Alkl- is -NHCH2CH2-, -OCH2CH2- or -NH-CH2CH(CHZOH)-.
[0293] In certain embodiments, for compounds of group XV, RZ1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is 0.
(0294] In certain embodiments, compounds of group XV have the structure:

C2alkyl~~NN N HN
~ 2alkyl N H HN-, HN~ r N
RI HN ~N N N S
.N Y N/ AJ O J
N\ I Ij N N
NJ , R3 (SP 69AI) (SP 70A1) CZalkyl N H H HN-~ ~C2alkyl ~ N H H HN--~
HN ~yN N N HN ~yN N N
S ~' S ~ \
Ra-fVN~ N O I Ra-NN N 0 I i or NJ
(SP 71A) (SP 72A) [02951 In certain embodiments, compounds of group XV have the structure:
~ Zalkyl N H H HN--1 ~ 2alkyi ~ N H H HN--1 Rxl HN NyN N R' HN ~~N N
NI N O I NN INI O J
NJ ~ NJ

(SP 69B1) (SP 70g1) CZalkyf N HN
C2alkyl N H H HN-~ HN ~~N~N N
Rxl HN' N N N N

~ S ~ l Ra-N N O
a-R N' r N' N N or Rxi (SP 71B1) (SP 72Bi) In certain embodiments, in the compounds having one of the structures (SP
69AI) through (SP 72A) and (SP 69B1) through (SP 72B) above, the C2alkyl moiety is optionally substituted; R1, R3 and R4 are independently hydrogen, lower alkyl or -CO2RlA where RIA is hydrogen or lower alkyl; and RXZ is hydrogen, lower alkyl or heterocyclyl. In certain exemplary embodiments, R~, R3 and W are independently hydrogen or methyl; and RXt is hydrogen, methyl or thienyl. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[02961 XVI. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

Z1) Alkj N(RZ~~m N~R W~~ HN
Alkl R1 ~ HN~ s N ~N N~N H
N~ H N N

(SP 72A) (SP 73A) ,_,Alkt N~/(RZ1)m Alk~ N~j~RZt)m W HN \ J Wi~ ~ NN,~
N ~ N NN ~ N I~ N-N
R4-N~ H R4-NH
N N N
(SP 74A) (SP 75A) Alk1 N~jtRZt)m Alk1 N-rj(RZt)m Rxt Wi~ )Z~N'L_-N HN Rt Wt~ % HN 'N NV NJ N& I NJ H

N
Rxt > >
(SP 72a) (SP 73g) t N (RZt)m Alkt N='/(Rzt)m Wt Alk ~ HN~
Rxt Wt~ I~ HN NI-N
~ N,~'N Ra_N H

N N or Rxt (SP 74B) (SP 75$) wherein R', R3, R4 and R~1 are as defined generally and in classes and subclasses herein; Wl is 0 or NRwl, where RW1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alkl is a substituted or unsubstituted CI_6aikylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -C02-, -C(=O)C(=0)-, -C(=0)NRL1A-, -OC(=O)-, -OC(=O)NRLIA-, NRLIANRLIB_, _ NRLIANRLIBC(=O)-, -NRLIAC(=O)-, -NRLIACO2-, -NRLIAC(_O)NRL1B_, _S(=O)-, -SO2_a _NRL1ASO2-, _SOZNRLIA_, -NRL1ASO2TqRL1B-, _O-, _S_, or -NRL1A_; wherein each occurrence of RLIA and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of Rz1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORZ2, _SRZ2, -W2Rz1, _S02NRzaRz3, -SOZRZ1, -C(=O)NRzzRzs, halogen, -CN, -NOZ, -C(=O)ORz3, -N(RZ2)C(=O)Rz3, wherein each occcurrence of RZ2 and Rz3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and e3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

[0297] In certain embodiments, for compounds of group XVI, -W'-A1k1- is -NHC1.6alkyl- or-OC1_6alkyl-. In certain embodiments, -W'-Alkl- is-NHC2alkyl-or -OC2alkyl-. In certain embodiments, -Wl-A1k1- is -NHCH2CH2-, -OCHZCH2- or -NH-CH2CH(CH2OH)-.
[0298] In certain embodiments, for compounds of group XVI, Rz1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is I and RZ' is C1 , F, methyl or -CF3. In certain embodiments, m is I and R7-1 is lower haloalkyl. In certain embodiments, m is 1 and Rz1 is -CF3.
[0299] In certain embodiments, compounds of group XVI have the structure:
/C2alky! N"' Rz1 HN H
Czalkyl N Rzl RT HN ( HN ~ N '\ ~~j N~
N
N N~N N~ H
N~ ( J H N N

(SP 72A1) (SP 73A) HN zalkyl HN RZ1 Czalkyl N Rzl ~ HN HN
N-. N NN N
R4-N i J H R4-N H
N or N
(SP 74A) (SP 75AI) wherein the C2alkyl moiety is optionally substituted; Rl, R3 and R4 are independently hydrogen, lower alkyl or --CO2RIA where R1A is hydrogen or lower alkyl; RZl is halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, RZl is Cl, F, methyl or -CF3. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[0300] In certain embodiments, compounds of group XVI have the structure:
N- Czalkyl N"_ Rzl R7 HN 2alkYl HN Rzi HN I~ HN_ ~/ z2 eN i/ h'\ N RZ N~ f~Nl NN R
N\ ( N ~ N NJ
; R3 (SP 72"Z) (SP 73A) Czalkyi N- Rza Czalkyl Nf Rzl HN~ HN HN HN R~ N )aN N Rzz R4-!J i J H R4-N, ,- ~ H
or N N

(SP 74A) (SP 75A) wherein the Caalkyl moiety is optionally substituted; RI, R3 and R4 are independently hydrogen, lower alkyl or -COZRIA where R IA is hydrogen or lower alkyl; Rz1 and RZ2 are independently halogen, lower alkyl or lower haloalkyl.
In certain exemplary embodiments, Rz1 and RZ2 are independently Cl, F, methyl or -CF3. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-. In certain embodiments, R21 and e are each Cl, F, methyl or -CF3, [0301] In certain embodiments, compounds of group XVI have the structure:
N
Czalkyl ~ Rzi C2alk yl ~ RZ1 Rx~ HN)aNY:5 ~ R~ HN"~ HN N~ N H
N 'N N~N
,N I N) N-' R3 ~ Rxl (SP 72$1) (SP 73B') C2alkyl N RZ1 P2alkyl N Rz1 HN HN
Rxl HN HN' ~ N~ N NIL-N

R4-N N ~ H ~ NJ
N or Rxi (SP 74BI) (SP 75B') wherein the C2alkyl moiety is optionally substituted; R', R3 and R4 are independently hydrogen, lower alkyl or -CO2RIA where R1A is hydrogen or lower alkyl; Rxi is hydrogen, lower alkyl or heterocyclyl; and RZ1 is halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, RXl is hydrogen, methyl or thienyl; and R~1 is Cl, F, methyl or -CF3. In certain exemplary embodiments, the C2alkyl moiety is -CHZCH2-.
[0302] In certain embodiments, compounds of group XVI have the structure:
C2alkyl N- RzI C2alkyl N RZ1 Rxl HN ~ HN' R' HN :::Q" ~/ hN RZ2 ~ IN Rzz N N,' 1 II H N~ j H
N N=~ N
R '3 Rx1 (SP 72BZ) (SP 738) CZalkyl N Rz~
CZalkyl N'/ Rzl HN'~ ~ HN~
Rxi HN HN-~ \ N N~N zz R
\ ~ ~N Rzz H
H

N N or Rxi (SP 74BZ) (SP 75B2) wherein the C2alkyl moiety is optionally substituted; Rl, R3 and W are independently hydrogen, lower alkyl or -CO2R1A where R IA is hydrogen or lower alkyl; e1 is hydrogen, lower alkyl or heterocyclyl; and RZi and RZ2 are independently halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, e1 is hydrogen, methyl or thienyl; and RZ' and RZ2 are independently Cl, F, methyl or -CF3. In certain exemplary embodiments, the C2alkyl moiety is -CHaCH2-. In certain embodiments, RZl and Rz2 are each Cl, F, methyl or -CF3.
[0303] XVII. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

Rzl~,Alkl R \4 N
Z4 - ~( )m W~ a " Aiki R \ R~ W~ ~ N -N ~ N f~ N~N N/ , J H
N~ ~ J H N N

(SP 76A) (SP 77A) Alk, Rz4 (RZ1)m ~ Alki Rz4 z1)m Wl ~ Wt ! ~ N
N ~v'N~
R4-N H R4_N, H
~J
N N N >
(SP 78A) (SP 79A) 1 R (Rz7)m A1k1 RZ\ ~ (RZ1)m Rxt Wt-'Alk \ ? N R' W1 '' N-'Ir =N N
N )"N
/ N N N
N~ N J H IV ~ H
R3 or Rx~
(SP 76B) (SP 77B) (Rzt)m Alki Rza -/(RZ1)m A
lk, R \4 '~~ Wi" N Rxi Wi N\~ N_ )::%- N
~ H
Ra_ R4 N ~N
H xt N N or R
(SP 78B) (SP 79B) wherein R', R3, R4 and Rx1 are as defined generally and in classes and subclasses herein; W1 is 0 or NRWI, where RWI is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; A1k1 is a substituted or unsubstituted C1.6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=O)-, 'C(=O)NRLIA-, -OC(=O)-, -OC(=O)NRLIA-~ NRL1ANRLIB-, -NRL1ANRLIBC(_O)-' -IVRLIAC(_O)-' -NRL1ACO2-, NRLIAC(=O)NRL1B-' -S(-O)-, -SO2-, -NRLIASO ' 'SO ~L1A- LIAS02NRL1B' L]A
2 , - 2 , -NR, -0-, -S-, or -NR-; wherein each occurrence of RLIA and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of Rzl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORz2, -SRZZ, -NRz2Rzs, _SO2NIzzRz3, -SO2RZ1, -C(=O)NRz2Rz3, halogen, -CN, -NO2, -C(=O)ORZ3, -N(RZ2)C(=O)RZ3, and wherein each occcurrence of Rz2, RZ3 and R Z4 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and Rz3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
[0304] In certain embodiments, for compounds of group XVII, -WI-A1k1- is -NHC1_6a1kyl- or -OC1_6alkyl-. In certain embodiments, -Wl-Alkl- is-NHC2alkyl-or -OC2alkyl-. In certain embodiments, -W1-Alkl- is -NHCH2CH2-, -OCH2CH2- or -NH-CII2CH(CH2OH)-.
[03051 In certain embodiments, for compounds of group XVII, RZ1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is 1 and RP
is Cl, F, methyl or -CF3. In certain embodiments, m is 1 and RZ1 is lower haloalkyl. In certain embodiments, m is 1 and RZ1 is -CF3. In certain embodiments, m is 2 and each occurrence of RZ1 is independently Cl, F, methyl or -CF3. In certain embodiments, m is 2 and each occurrence of RZ1 is Cl, F, methyl or -CF3. In certain embodiments, m is 2 and each occurrence of Rz1 is F.
[0306] In certain embodiments, for compounds of group XVII, RZ4 is hydrogen, or lower alkyl. In certain embodiments, RZ4 is lower alkyl. In certain embodiments, RZ4 is isopropyl.
[0307] In certain embodiments, compounds of group XVII have the structure:

zRzT
'-~
Czalkyi VN
Czalkyl RzRzI HN Ri HN' ' \ N ~%~NN~ I N N, I J H N N~

R
(SP 76A) (SP 77A) C2alkyl Rz4 Rzl C2alkyl Rza ' Rza HNJ I N HN' \ 'N \ I
N~ N ~N~N ~ N N~N
Ra-N H Ra-N. ,- J H
or N N
(SP 78A) (SP 79A1) wherein the C2alkyl moiety is optionally substituted; RI, R3 and R4 are independently hydrogen, lower alkyl or -CO2RIA where R IA is hydrogen or lower alkyl; RZ1 is halogen, lower alkyl or lower haloalkyl and R24 is hydrogen or lower alkyl. In certain exemplary embodiments, RZ' is Cl, F, methyl or -CF3 and RZ4 is hydrogen or isopropyl. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[03081 In certain embodiments, compounds of group XVII have the structure:
Czalkyl RZ4 Rz~
1 HN2afkyl Rz N Rz1 HNN ZP
~
N 'N N~N Rz2 N/ l/N H R
N ( H N NJ
N , R3 (SP 76A) (SF 77A) ~- ' RzI
HN CZalkyl Rz NQ-~ Rzl HN C2alkyl Rza i \ ~
N z N _ Rz2 R4-N H Ra-N. H
N or N N
(SP 78A) (SP 79A2) wherein the C2alkyl moiety is optionally substituted; R', R3 and Ra are independently hydrogen, lower alkyl or --CO2R1A where RIA is hydrogen or lower alkyl; RZ' and RZZ are independently halogen, lower alkyl or lower haloalkyl and e is hydrogen or lower alkyl. In certain exemplary embodiments, RZl and e are independently Cl, F, methyl or -CF3; and RZ4 is hydrogen or isopropyl. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-. In certain embodiments, Rz1 and RZ2 are each Cl, F, methyl or -CF3.

j03091 In certain embodiments, compounds of group XVII have the structure:
C2a1kyl Rza xl HN N "_ Rzl Ra HN C2alkyl V za ~ Rz' ~~
R ~ ~N~ ~~ .r-=
N
N, N Nj H N~ I N J lj H

R3 . Rxl ~ a (SP 76gj) (SP 77g') _ CZalkyl Rza RZt \
Rx1 HN CZalkyl Rza / Rzti HN I~ 'N
N ~ ,Nt \ N N~N
Ra-N H
Ra N. H -~ N~
N N or Rxt (SP 7$B) (SP 79B1) wherein the C2alkyl moiety is optionally substituted; R1, R3 and R4 are independently hydrogen, lower alkyl or -COzRIA where R1A is hydrogen or lower alkyl; Rxl is hydrogen, lower alkyl or heterocyclyl; Rz1 is halogen, lower alkyl or lower haloalkyl and RZ4 is hydrogen or lower alkyl. In certain exemplary embodiments, e1 is hydrogen, methyl or thienyl; RZI is Cl, F, methyl or -CF3;
and RZ4 is hydrogen or isopropyl. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[0310) In certain embodiments, compounds of group XVII have the structure:
C2a)kyl VN' R C2aikyl Rza Rxl HN R~ HN'~ ,N~ ~ N N RZZ N N N-N RZ2 N I ~ H N\ ~ ~ H
N N N
=
R3 . Rx7 a , (SP 76B) (SP 77B) C2alkyl Rz'a / Rz1 Czaikyl R? N Rzi HN J~
Rxl HN ~ ~ z2 N= ~% ~ N R
R~ Ra-N N H
-N H ' %J
Ra N I
N Nf or RXI
(SP 78Ba) (SP 79BZ) wherein the C2alkyl moiety is optionally substituted; R', R3 and Ra are independently hydrogen, lower alkyl or -CO2R1A where RIA is hydrogen or lower alkyl; RXl is hydrogen, lower alkyl or heterocyclyl; RZj and RZa are independently halogen, lower alkyl or lower haloalkyl and R Z4 is hydrogen or lower alkyl.
In certain exemplary embodiments, Rxl is hydrogen, methyl or thienyl; RZl and RZ2 are independently Cl, F, methyl or -CF3 and Rz4 is hydrogen or isopropyl. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-. In certain embodiments, Rzl and RZ2 are each Cl, F, methyl or -CF3.

[0311] XVIII. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

(RY1)q (R )q RW2 RW2 Rwi ~AIk1 i R~ RwlNAlki N OZ\ R\ N NOz, Z
Z NN O
N N J O N~
J J
N~ ~ r N
N Rxl (SP 80A1) (SP 80B1) ~RY1)p (RY7)q Rw1 rAlk1 ~2 -~1 W3 W4 R1 Rw1N Alk, ~2. -~1 Q RWS RW4 R\ N ~ \0 RR
N ~ N N Z
' tV N J N/~J'NZ N~ ~ J RW2 RW2 N R'W2 RW2 N
N Rxl (SP 80AZ) lia (SP 80 ) (RY14j22.-J RW3 (RY1)a RW3 RW4 RW2 RW4 RW2 Rw1 Alk, j2 - J\
~wT Alk1 1 R ~ N I Z
R; N Z ~ N JO

NN 1N O & I N~
\ NJ Rxa > >
(SP 80A3) (SP 80B3) wherein Rxl and Z are as defined generally and in classes and subclasses herein; RI and RWI taken together form an optionally substituted 5- to 6-membered ring; Alkl is a substituted or unsubstituted Cl-6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -C02-, -C(=O)C(=O)-, -C(=O)NRL'A-, -OC(=0)-, -OC(=O)NRL1A_' -NRL1ANRL1B_' -NRLIANRLIBC(_O)_~ _NpL1AC(7O)-~ _NRL1ACOa-, -NRLIAC(_O)NkL1B_, _S(=O)-, -SO2-, NRLIASO2-, -SO2NRL1A-, NRLIASO2NRL1B_' -0-, -S-, or NRLIA-; wherein each occurrence of RLIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3; Jl, Ja and J3 are independently 0, S, N, NRYI or CRYf;
wherein each occurrence of RYl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORY3, -SRY3, -NRv2RY3, -SOZNR~2RY3, -C(=O)NRY1RY3, halogen, -CN, -NOZ, -C(=O)ORY3, -N(R.Y2)C(=O)RY3, wherein each occcurrence of RY2 and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RY2 and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ririg; G2 is absent, 0 or NRG2; RW3 and RW4 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; and RW2 and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
[0312] In certain embodiments, for compounds of group XVIII, -Wl-A1k1- is -NHC1.6alkyl- or -OC1-6alkyl-. In certain embodiments, -W'-Alkl- is-NHC2alkyl-or -OC2alkyl-. In certain embodiments, -V6T1-A1k1- is -NHCH2CH2-, -OCH2CH2- or -NH-CHZCH(CH2OH)-.
[0313] In certain embodiments, compounds of this class have the structure -(SP
80A4'6), or (SP 80B4-6) below:

Y1)q Rw2 (RY)Q (R
RW2 ~ \l5alky~J 'N~-N G
\ NiI salkyl iN G2 F ~ 2~Z
y ~Z N N G
N G N~ J
N~ ~ J N
Rxl (SP 80A) (SP 80g4) ~RY1)Q
(RY1)Q 1 Rw4 4"~2- RN~1-salkyl J2 -J 0 RW3 z il.salkyl p Rw~RW4 J
RN N
~ N ~N ~ N N N N z \ ~ RW2 Rw2 N ~ J Rw2 RW2 N
N Rxz (SP 80A) (SP 80B5) (RY1} q RW3 (RY1) Rws RW4 Rw2 q Rwa RW2 R C1~alkyl Jz. _J1 N
\N C1_salkyl J2. -Jti N'Z rN~- j~ ~Z
! JJ 0 ,N N O
N N N + I

N~ + N RX1 N~' (SP S0A6) (SP 80$g) wherein the C 1_6alkyl moiety may be substituted or unsubstituted.
[0314] In certain embodiments, for compounds of formulae (SP 80A4"6) and (SP
80B4') the C1.6alkyl moiety is a substituted or unsubstituted Caalkyl moiety.
In certain exemplary embodiments, the Cz_6alkyl moiety is -CH2CH2-.
[0315] In certain embodiments, in compounds of formulae (SP 80"'l-6) and (SP
80B1-6) the 5-membered ring having the structure:

~=y 2 -J' .
(RY1 )q, has one of the following structures:

RYl N '~. N A N,,~:

R
[0316] In certain embodiments, -N(RW2)C(=O)G2- is NHC(=O)-, -NHC(=0)O-, or -NHC(=O)NH-. In certain embodiments, N(RW2)C(=0)N(RW2)CRW3RW4- is NHC(=O)NHCH2-, and CRW3RW4C(=O)N(RW) - is -CHZC(=O)NH-.
[0317] XIX. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

Y1 (RY1)q 4 RW2 ~R }q J4 RW2 Rw1 Alk,N G
1 Rw~ N Alk,~~ ~~N G2 Rl N j1s ~~
J ~2 _Z
R \ ~, Z N s p N J O N, N ~ I N Rx1 ~

(SP 81Aj) (SP 81B1) (RY1)9 0 R W3 RW4 Y1 RW3 RW4 ~~J~
(~ >9G~,1 ~ RW1 ,,AIk1 ~~5 ~ ~N Z
Rw~ ~AIk1 N N z R1 N J~J6~ RW2 RW2 R1 N JlJs~ RWZ AW2 .
N
NN ~ N N I NJ
. ~
~ ; RX1 (SP 81A) (SP 81"2) (RY1)RW3 RY1 RW3 ~ J~ RW4 RW2 ~ ~q RW4 W2 ~
\J R' Rw1 AIk ~ ~ N
Rw1 AIk1-; ~ ~ l N R N Js ~ Z
R; N J-Js Z N N O
NN + ~N+ O N\ NJ
\ NJ RX1 (SP 81A) (SP 81B) wherein RXI and Z are as defined generally and in classes and subclasses herein; R' and RWI taken together form an optionally substituted 5- to 6-membered ring; A1k1 is a substituted or unsubstituted CI_6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -C02-, -C(=0)C(=0)-, -C(=O)NRLIA-, -OC(=O)-, -OC(=O)N.RL1A_i -NRLIANRLIB_~ ~L1ANRLIBC(=O)-, -NRLIAC(~O)_, -NRLIACO2-,--NRLIAC(=O)NIL1B_, _S(=O)_, -SOa-, NR&]ASO2-, -SOzNRLIA_, _W IASOzNRLSB_o -0-, -S-, or -NRLIA-; wherein each occurrence of RL1A and RL1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3; J4, J5 and J6 are independently N or CRy; wherein each occurrence of RYl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORY3, -SRY3, NRYZRY3, -SO2NRRy3, -C(=O)NRy2RY3, halogen, -CN, -NO2, -C(=O)ORY3, N(R~'2)C(=O)RY3, wherein each occcurrence of RYZ and RY3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RYZ and RY3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; G2 is absent, 0 or NR 2; RW3 and RW4 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; and RW2 and RG2 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.

103181 In certain embodiments, for compounds of group XVIII, -W'-Alkt- is -NHC1_6alkyl- or -OC1_6alkyl-. In certain embodiments, -W'-Alkl- is-NHC2alkyl-or -OCaalkyl-. In certain embodiments, -Wl-Alkl- is NHCH2CHa-, -OCH2CH2- or -NH-CH2CH(CH2OH)-.
[03191 In certain embodiments, compounds of this class have the structure (SP
S0A4-6), or (SP 80B4"6) below:

(RY1) N wz.
(RY1)q\ J\ R W2 R C_satkyl J
G
\N C,alkyt ;5 N G2, (N~ J~Js y Z~z ~j8 y Z N N O
N N O N\
N~ N
N Rx1 ;

(SP 81A4) (SP 81B) (RY1)44 p Rw3 RW4 CRYl,~~31 ~N~wa C alk l N
R C_ alk 1( N N Z R=~ ~-~-s y~~5 r\~N ~ s Y 3\JB- RW2 R~ N Rw2 Rwz IN N I

(SP 8IA) (SP SIBS) Y1 ws (RY1)q J4R~ RW4 W2 'R )q\J; Rwa RW2 R C1~alkyl ~
R \ N
~N~C,1_sa(kyl J5 ~ N\ r~ N ~~ ~'Z
~ ~s~ z lN N o N~ ( N~
= NJ Rx1 (SP SIA6) (SP 81B6) wherein the C1.6alkyl moiety may be substituted or unsubstituted.
[03201 In certain embodiments, for compounds of formulae (SP 81A4-6) and (SP
8].84-6) the C2 .6alkyl moiety is a substituted or unsubstituted C2alkyl moiety. In certain exemplary embodiments, the C1_6alkyl moiety is -CH2CH2-.
[0321] In certain embodiments, in compounds of formulae (SP 81A1"6) and (SP
81111"6) the 6-membered ring having the structure:
J4 (RY1)q y j6~
J5 .~

has one of the foIlowing structures:

(RY1)q\\ (RY'I)N\~

103221 In certain embodiments, N(RW2)C(=O)G2- is -NHC(=O)-, NHC(=0)O-, or NHC(=O)NH-. In certain embodiments, -N(RN'2)C(=O)N(Rw2)CRw3Rw4- is NHC(=0)NHCH2-, and -CRw3RwaC(_O)N(RW2) - is -CH2C(=O)NH-.

[0323] XX. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

Rz1 RW~ Alki N=~j{RZ1)m R1 RWtN, Alk1 HN { )m Ri N~ ~ HN
N ~
N 'N ):)'N'~ ' N N I N N
N~ H N
N or Rxl (SP 82) (SP 83) wherein Rxl is as defined generally and in classes and subclasses herein; R' and Rw' taken together form an optionally substituted 5- to 6-membered ring;
Alk, is a substituted or unsubstituted C1_6alkylene or C2_4alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -C.:Oz-, -C(=O)C(=O)-, -C(=O)NRLIA-, -OC(--O)-, -OC(=0)NR LlA-~ NRLIAiqR LIB-, -NRL'ANRLiBC(=O)-, -NRL>nC(=O)-, NRLiACO2-, NRL'AC(=O)NRLIB-, --S( O)-, -SO2-, -NRL1ASO2-, -S02NRL1A- -NRL1ASO2NRLIB-, -0-, -S_, or -NRL1A-; wherein each occurrence of RLIA and RLtB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from I to 4; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORz2, -SRz2, Nlz2Rz3, -SO2NRzzRz3, -S02RZ1, -C(=O)NRz2Rz3, halogen, -CN, -NOa, -C(=0)ORZ3, N(Rz2)C(=O)RZ3, wherein each occcurrence of RZ2 and Rz3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and e3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

[03241 In certain embodiments, for compounds of group XX, -W'-Alkj- is -NHC1_6alkyl- or -OC1_6alkyi-. In certain embodiments, -W'-Alkl- is-NHC2alkyl-or -OC2alkyl-. In certain embodiments, -Wl-Alkl- is NHCHZCH2-, -OCH2CH2- or -NH-CH2CH(CH2OH)-.
[0325J In certain embodiments, for compounds of group XX, RZl is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is I and RZl is H, Cl, F, methyl or -CF3. In certain embodiments, m is 1 and RZ1 is hydrogen.
[0326] In certain embodiments, compounds of group XX have the structure:
R\~N~CZalkyi HN \ N ~ Rzl N N N''''N
N~ H
N
(SP 82A) wherein R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; and RZI is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, Rz1 is hydrogen, Cl, F, methyl or -CF3. In certain exemplary embodiments, RZI is hydrogen. In certain embodiments, R is hydrogen.
[0327] In certain embodiments, compounds of group XX have the structure:
N
~
C2alkyl HN
\~ N 1- Rz~
r } \ ~
IN /-'N
N N N
N
Rxl (SP 83A) wherein R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; Rxl is hydrogen, lower alkyl or heterocyclyl; and RZ1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, R is hydrogen or lower alkyl; RXl is hydrogen, methyl or thienyl; and RZ' is hydrogen, Cl, F, methyl or -CF3. In certain exemplary embodiments, R and RZI are each hydrogen; and 01 is hydrogen, methyl or thienyl.

[0328] XXI. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

Rwi ---Alki, /; ~N
R N H
Rwt~Alkt_ ~ \ Ri N -g ~ ~ Rzt S Y N 0 t ~ ~ )m NN N o I~ ~RZi)m N~ J
. N
~
N or Rxi (SP 84) (SP 85) wherein Rxl is as defined generally and in classes and subclasses herein; RI
and RWI taken together form an optionally substituted 5- to 6-membered ring;
Alkl is a substituted or unsubstituted C1.6alkylene or C2.6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -CO2-, -C(=O)C(=0)-, -C(=O)NRLIA-, -aC(=O)-, -OC(=O)NRLIA_~ -~aL1ANRLIB- -NRLIANRLIBC-,(,Ol-, NNRLIAC( O)-, NRLIACO2- -NRLIAC('O)~L1B-, _S(=O)_~ -SO2-, -NRLIASO2-,l -SO2NRLIA-, _NRLIASO2iqRLIB-, -0-, -S-, or NRLIA-' wherein each occurrence of RLIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORz2, _SRz27 -NRzaRz3, -SO2NRzzRz3, -SO2RZ1, -C(=O)NRZZRZ3, halogen, -CN, -NO2, -C(=O)ORZ3, -N(Rz2)C(=0)RZ3, wherein each occcurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, hetero l, -~'Y
(alkyl)aryl, -(alkyl)heteroaryl or acyl, or Rza and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
[0329] In certain embodiments, for compounds of group XXI, -WI-AIkI- is -NHC1_6alkyl- or -OC1_6a1ky1-. In certain embodiments, -WI-Alkl- is-NHC2alkyl-or -OC2alkyl-. In certain embodiments, -WI-Alkl- is -NHCH2CH2-, -OCH2CH2- or -NH-CH2CH(CHZOH)-.
[0330] In certain embodiments, for compounds of group XXI, Rzl is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is 1 and RZI is Cl, F, methyl or -CF3. In certain embodiments, m is I and RZ1 is lower haloalkyl. In certain embodiments, m is 1 and RZ1 is --CF3. In certain embodiments, m is 2 and each occurrence of RZ1 is independently CN, Cl, F, methyl or -CF3. In certain embodiments, m is 2 and each occurrence of Rzi is CN, Cl, F, methyl or -CF3.
In certain embodiments, m is 2 and one occurrence of Rzl is Cl, F, methyl or -CF3 and the other is CN.
[0331] In certain embodiments, compounds of group XXI have the structure:
R CZaIkyl N H R C2alkyi N H
N/ ~yNN \ Rz1 N ~NN \ Rzi NIN N Q I/ Iaj N Q I~ CN
\ I N) N N
(SP 84A) (SP 84A) R CyalkyI ~ N H H R CZalkyi N H
Rzi \.. Nr ~y N~N \ Rzl N ~N O(CN
Q I/ N ~N IV~ ! NJ N' ! N I

RX' or Rxi J "

(SP 85A) (SP 85A) wherein the C2alkyl moiety is optionally substituted; R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; RXl is hydrogen, lower alkyl or heterocyclyl;
and RZl is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, Rxl is hydrogen, methyl or thienyl; and R~1 is hydrogen, Cl, F, methyl or -CF3. In certain exemplary embodiments, in compounds of formulae (SP
84A) and (SP 85A), Rzl is hydrogen. In certain exemplary embodiments, in compounds of formulae (SP 84A2) and (SP 85A), RZ1 is Cl or -CF3. In certain embodiments, R is hydrogen. In certain exemplary embodiments, the Caalkyl moiety is -CH2CH2-.

[0332) XXII. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):
Rw~ /AIkI ~ N H H HN-1 Rwi ~ Alki N H H HN--1 RI N ~yN N ' N
R N I N N N S ~ ._ _ zi NN N 0 C _ (RZ1)m N~ ~ O ~ , ZR )m J N
N or RXl (SP 86) (SP 87) wherein kXl is as defined generally and in classes and subclasses herein; R' and RW' taken together form an optionally substituted 5- to 6-membered ring;
Alki is a substituted or unsubstituted C1_6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -C02-, -C(= O)C(=O)-, -C(=O)NRL1A-, -OC(=O)-, -OC(=O)NRL1A-' -NRLtAW1B-, -NRLIANRLIBC(==O)_' ~NRLIAC(=O)-, -NRLtACO2-, -NRL]AC(_O)NRL1B_, _S( Q)-, -SO2-, -NRLIASO2_, _SOZNRLIA-, qqRL1ASO2mkL1B_, -0-, -S-, or -NRLfA-; wherein each occurrence of R LIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of Rzl is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORZ2, -SRz2, _ NeaRzs, -S02NRzzRz3' -SO2RZ1, -C(=O)NRz2'RZ3, halogen, -CN, -N02, -C(=0)ORz3, -N(RZ2)C(=O)RZ3, wherein each occcurrence of Rz2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and e3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
[0333] In certain embodiments, for compounds of group XXII, -WI-A1k1- is -NHCI.6alkyl- or -OCI_6alkyl-. In certain embodiments, -W'-Alkl- is-NHCaalkyl-or -OC2alkyl-. In certain embodiments, -W1-Alkl- is NHCH2CH2-, -OCH2CH2- or -NH-CH2CH(CH2OH)-.
103341 In certain embodiments, for compounds of group XXII, RZ1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m_ is 0.

(0335) In certain embodiments, compounds of group XXII have the structure:
R C2alkyl N H H HN--1 R CZa1k~N,, _H H HN-1 ~~N N N ~ N
N ~'N N ~ N S
I
~ { { N O /
a\1 N O /
~N
N ' RRl =
(SP 86A') (SP 87A) wherein the C2alkyl moiety is optionally substituted; R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; and RXl is hydrogen, lower alkyl or heterocyclyl. In certain exemplary embodiments, Rxl is hydrogen, methyl or thienyl. In certain embodiments, R is hydrogen. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[0336) XXIII. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):

RWt / Alkt N~ H
N N
Rwt ~ Ikt N~ H R1 N~,/
R' N N"~/N I~(RZt)m N N IOf j(Rzt)m N ~ N (0~ N~ NJ

N\ N Or Rxt (SP 88) (SP 89) wherein R~1 is as defined generally and in classes and subclasses herein; RI
and RW1 taken together form an optionally substituted 5- to 6-membered ring;
A1k1 is a substituted or unsubstituted C1_6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -C02-, -C(=O)C(=O)-, -C(=O)NRLIA_, -OC(-0)-, -OC(=O)NRL1A_, _NRLIANRLIB_' -NRLIAI~RLIBC(=O)_' -IqRLIAC(_O)-, -NRL1ACO2-, -NRLIAC(=O)NRLIB-2 _S(=O)-, -502-, -NRLIASOa-, -SOzNRL IA-, -NRL1AS02NRLI11- -0-, -S- or -NRLIA
-; wherein each occurrence of RLIA and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORZ2, -SRz2, -NRZ2Rz3, -SO2NRz2Rz3, -SO2Rz1, -C(=0)NRz2Rz3, halogen, -CN, -NO2, -C(=O)ORZ3, -N(RZZ)C(=O)RZ3, wherein each occcurrence of R Z2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, (alkyl)aryl, -(alkyl)heteroaryl or acyl, or Rz2 and RZ3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
[0337] In certain embodiments, for compounds of group XXIII, -W3-Alk1- is -NHC1_6alkyl- or -OC1_6alkyl-. In certain embodiments, -W'-Alkl- is-NHC2alkyl-or -OC2alkyl-. In certain embodiments, -WI-Alk1- is -NHCH2CH2-, -OCH2CH2- or -NH-CH2CH(CHZOH)-.
[03381 In certain embodiments, for compounds of group XXIII, RZ1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain embodiments, m is 1 and RZI is Cl, F, methyl or -CF3. In certain embodiments, m is I and RZ1 is lower haloalkyl. In certain embodiments, m is 1 and RZ1 is -CF3. In certain embodiments, m is 2 and each occurrence of RZI is independently CN, Cl, F, methyl or -CF3.
In certain embodiments, m is 2 and each occurrence of RZ1 is CN, Cl, F, methyl or -CF3. In certain embodiments, m is 2 and one occurrence of RZl is Cl, F, methyl or -CF3 and the other is CN.
[0339] In certain embodiments, compounds of group XXIII have the structure:
R CZaIkyl N H R CZalkyi N- H
('~N~ ~N ' \ Rz~ ~N/ ~N~N Rz1 IN N O N N O CN
N\ NN I J
N
(SP 88AI) (SP 88A) R Czalkyl N=l H z, R C2aIkyl N H

N~N R N\~N/ ~N Rz1 Nt ~ N CN
N~ + NJ IV~ ~ NJ
Rxi ; Rx1 (SP 89AI) (SP 89A2) wherein the C2alkyl moiety is optionally substituted; R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; RxI is hydrogen, lower alkyl or heterocyclyl;
and RZI is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, Rxl is hydrogen, methyl or thienyl; and R~1 is hydrogen, Cl, F, methyl or -CF3. In certain exemplary embodiments, in compounds of formulae (SP
88A) and _(SP 89A), Rzl is hydrogen. In certain exemplary embodiments, in compounds of formulae (SP 88A) and (SP 89A) , Rz1 is Cl or -CF3. In certain embodiments, R is hydrogen. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[0340] XXIV. Compounds having the structure (and pharmaceutically acceptable derivatives thereo#):

RI RiNAlkl - N \
Rw1 / Alki N \ / ~ ~Rzi~m R' N \ / ~ ' ~ ~Rz1jm J~ ~ N O /
NN N O N
I NJ
N or RXl (SP 90) (SP 91) wherein Rxl is as defmed generally and in classes and subclasses herein; R' and RWl taken together form an optionally substituted 5- to 6-membered ring;
Alkl is a substituted or unsubstituted C1_6alkylene or C2_6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=0)-, -CO2-, -C(=O)C(=O)-, -C(= O)NRLIA-, -OC(=O)-, -OC(=O)NRL1A-' NRLIANRLIB-, -NRLIANRLIBC(=O)-, -NRLIAC(=O)-, -NRLIACO2-, -NRLIAC(_O)NRL1B_' _S(=O)-, _ SO2-, -NRLIASO2-, -SOZNRLIA-, -NRLIASO2NRL1B-, -0-, -S-, or -NRL1A_; wherein each occurrence of RL1A and RLIB is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of RZ1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -ORZ', -SRZ2, -NRZ2Rz3, -SO2NRzzRz3, -SO2Rz1, -C(=O)NRz2Rzs, halogen, -CN, NOz, -C(=O)ORZ3, -N(Rz2)C(=O)Rz3, wherein each occcurrence of RZ2 and RZ3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or RZ2 and e 3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.
(0341] In certain embodiments, for compounds of group XXIV, -W1-Alkl- is -NHC1_6alkyl- or -OCl-6alkyl-. In certain embodiments, -W'-Alkl- is-NHC2alkyl-or -OC2alkyl-. In certain embodiments, -Wl-A1kI- is -NHCH2CH2-, -OCH2CH2- or -NH-CH2CH(CH2OH)-.
[0342] In certain embodiments, for compounds of group XXIV, RZl is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain- embodiments, m is 1 and RZ1 is Cl, F, methyl or -CF3. In certain embodiments, m is 1 and RZl is lower haloalkyl. In certain embodiments, m is 1 and RZ1 is -CF3. In certain embodiments, m is 2 and each occurrence of Rz1 is independently CN, Cl, F, methyl or -CF3.
In certain embodiments, m is 2 and each occurrence of RZl is CN, Cl, F, methyl or -CF3. In certain embodiments, m is 2 and one occurrence of RZ1 is Cl, F, methyl or -CF3 and the other is CN.
[0343] In certain embodiments, compounds of group XXIV have the structure:
R C2alkyl H Z1 R C2alkyl H \/ N I~ R N~R~' C ' IN N C CN
IN N ~
N~ I J
N N
(SP 90A1) (SP 90A) R C2alkyi ti z1 R CZafkyl - H zi N ~ ~ N ( R N ~~ N R
IN N C N N d C CN
NJ N~ I NJ

Rx' or Rxl ia (SP 91A1) (SP 91A) wherein the C2alkyl moiety is optionally substituted; R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; Rxl is hydrogen, lower alkyl or heterocyclyl;
and RZ1 is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain exemplary embodiments, Rxl is hydrogen, methyl or thienyl; and RZ1 is hydrogen, Cl, F, methyl or -CF3. In certain exemplary embodiments, in compounds of formulae (SP
90A1) and (SP 91A), Rzl is hydrogen. In certain exemplary embodiments, in compounds of formulae (SP 90A) and (SP 91A), Rzl is Cl or -CF3. In certain embodiments, R is hydrogen. In certain exemplary embodiments, the C2alkyl moiety is -CH2CH2-.
[03441 XXV. Compounds having the structure (and pharmaceutically acceptable derivatives thereof):
RWQ, ~AIkl, ,L2 RW~N~AIki,Y,L~ N Y Z
Z
R~N N N, I J
N, ( J N3 N
N R
(SP 92) (SP 93) RW~N~ AIkl.Y.L~ z RW..1~N~-AIkl.~,-L~Z
N- ~ N .' ~ N
R4'N ~ J R4'N. ~ J
N or N N N
(SP 94) (SP 95) wherein R', R3, R4, L2, Y and Z are as defined generally and in classes and subclasses herein; and RW i together with a carbon atom present on Alkl forms an optionally substituted 5- to 6-membered heterocyclic ring.
103451 In certain embodiments, compounds of the invention have one of the structures (SP 92A) - (SP 95A) below:
Y'L2~Z
Z m YL2 Ratki N
RAIk1 N ~~
RNN I" N N N
/ ~ I
\ J N3 NJ
N R
(SP 92A) (SP 93A) m Y-L2'Z !' "mJ Y~Lz-'Z
RAI10 RAlk1!
N N
~N ~ ~N
Ra-N J R4-N. ~ ~
N or N N
(SP 94A) (SP 95A) wherein m is 1 or 2 and RAIkl is hydrogen, halohen, hydroxy, CN, nitro, lower alkyl, lower alkoxy, aryl, or heteroaryl. In certain embodiments, RAlkl is hydrogen.
[0346] In certain embodiments for compounds as described in subgroups I-XVII
and XXV above, Rl, R3 and R4 are independently hydrogen or lower alkyl. In certain embodiments, R', R3 and R4 are independently hydrogen. In certain embodiments, R', R3 and R4 are independently hydrogen, methyl, ethyl, isopropyl or one of:
(CH2)2 (CH2)3 (CH2)2 (CH2)3 (CH2)2 (CH2)3 HO~ HO' H2N' H2N~ ~~,s RTA-R1g RtA-N"
RIB

(CH2)2 (CH2)3 (CH2)2 (CH2)3 N/ X, Ni Y N~ N~ ~~'s 0 0 0 0 wherein R IA
and R1B are independently hydrogen, methyl or ethyl.
[0347] In certain embodiments, for compounds as described in subgroups I-XXV above, RW I together with a carbon atom present on Alkl forms an optionally substituted 5- to 6-membered heterocyclic ring.
[034$} In certain embodiments, for compounds as described in subgroups I-XIII, XVIII-XIX and XXV above, Z is a branched alkyl, alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety. In certain exemplary embodiments, Z has one of the following structures:

RZ1 RZ1 Rzl Rz' :~k ORz1 N I I N, Rz' N.Rz1 wherein each occurrence of Rz1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl. In certain embodiments, Z has one of the following structures:

N Y
Y
N
,r.
[0349] In certain embodiments, for compounds as described in subgroups 1-XIII, XVIII-XIX and XXV above, Z is a cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl moiety. In certain exemplary embodiments, Z has one of the following structures:
Rzl Rzl x5Z4 R
zT ~. Rz' \ , \ N

HN \ / Rzt HN Rzl ~ \ ~ Rz' '~~\N 7', N
wherein RZ' is Cl, F, methyl or CF3; and RZ4 is hydrogen or cyano.
[0350] In certain embodiments, for compounds as described_in subgroups I, IV-VI and XXV above, -L2-Z together represent a moiety having one of the following structures:

N-7~N Rzl \ / Rzt Rzl \ \ ' Rz~
H' Rz1 H \N H H

wherein Rz1 is Cl, F, methyl or CF3.
[0351] It will also be appreciated that for each of the subgroups I-XXV
described above, a variety of other subclasses are of special interest, including, but not limited to those classes described above i)- clxxiv) and classes, subclasses and species of compounds described above and in the examples herein.
[0352] Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided.
[0353] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers. In addition to the above-mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.
[0354] Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may exist as one or a combination of polymorphs of compound of general formula (I) forming part of this invention. For example, different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques. Thus, the present invention encompasses inventive compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
[0355] 2) Synthetic Overview:
[0356} The practitioner has a a well-established literature of pyrazolo pyrimidine chemistry to draw upon, in combination with the information contained herein, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the synthesis of the compounds of this invention, including compounds containing the various Rz and R3 substituents and L', L2, Y and Z moieties.

[0357] Moreover, the practitioner is directed to the specific guidance and examples provided in this document relating to various exemplary compounds and intermediates thereof.
[0358] As described above, the present invention provides novel compounds, specifically compounds having the following general structure:

L1-Y-,L2,,,Z
A B~
N RZ
(1) wherein A-B together represent one of the following structures:

/tA N Xis ' N
~ RQ,N /
~
N R2 or X3 N R
and pharmaceutically acceptable derivatives thereof;
wherein R2, R4, XIA, XZA, X1B, X2B, L', L2, Y and Z are as defined in classes and subclasess herein.
=[0359] It will be appreciated that for compounds as generally described above, certain classes of compounds are of special interest. For example, one class of compounds of special interest includes pyrazolo pyrimidines having formulae (IA) though (IA4):

L1--Y-,L2'Z
Rl O_y-L2'Z Ll_'y~ 2'Z
N~ N L
N N ~N ' 2 N' ~N
N~ I! N R Ra_N
N R2 , R3 , N R2 or LI-YIL2rZ
a N~
R --N''' !'~
N

Wi) rIA2) lTA3) OA4) [0360] In yet another laspect of the invention, methods for producing intermediates useful for the preparation of compounds of formulae (I) and ~A) though (IA4) are provided, embodiments of said methods being depicted generally in Scheme A:

LG' L'Y,Lz'Z
A BN L1A'Y~ L2" Z BI
N R2 N Rz 0) (~) Scheme A
where LG' is a suitable leaving group and LIA is adapted to displace LG1 upon reaction with pyrazolo pyrimidine (1).
[0361] In certain embodiments, the methodology may be used to generate inventive compounds of the general formula (I):

Wi -,AIkj.Y.L:Z
A BzN
Nr R2 (IB) wherein W1 is 0 or NRWy, where RW1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and A1kl is a C1_ 6alkylene or C2_6alkenylene moiety.
103621 In yet another aspect of the invention, methods for producing intermediates useful for the preparation of compounds of Formula (Icx) and (Icz) wherein W I is -C(=0)N(Rwl)-, where RWi is as defined above, are provided, embodiments of said methods being depicted generally in Scheme B:
R, wi 0 OH O N= .Y' zeZ
H2N\ Z Alkti L
AIk~Y~Lz ~
A B N ---- - A B N
N R2 -----= N%~Rz (2) Sc{ieme B
(0363] Numerous suitable prodrug moieties, and information concerning their selection, synthesis and use are well known in the art. Examples of prodrug moieties of interest include, among others, prodrug moieties that can be attached to primary or secondary amine-containing functionalities. For instance, prodrug moieties of interest include those that can be attached to group IVIH2. Examples of such prodrug moieties include the following:

0 Q For the synthesis of the prodrug groups, see Borchardt, R.T. et ai , NH2 J. Org. Chem. 1997, 62, 1356-1362 and 1363-1367.

R' = all natural, unnatural amino acids ~N For the synthesis of the prodrug groups, see Rr O Z~ Zhou, X-X. et. a1., PCT WO 99151613.
R
R' = C1-C4 alkyl, cycloalkyl, oxyalkyl, aminoalkyl, etc.
R2 = all natural, unnatural amino acids ~ For the synthesis of the prodrug groups, see Ezra, A. et. al., NHZ J. Med. Chem.2000, 43, 3641-3652.
~ O
R1, Ra = all natural, unnatural amino acids [0364] The present invention encompasses any prodrug form of the compounds described herein. Although certain other exemplary prodrug moieties generated from the inventive compounds amino group are detailed herein, it will be appreciated that the present invention is not intended to be limited to these prodrug moieties; rather, a variety of additional prodrug moieties can be readily identified by a person skilled in the relevant art.
[0365] 3) Pharmaceutical Compositions 103661 As discussed above, the present invention provides compounds that are inhibitors of protein kinases (e.g., Aurora kinase), and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to melanoma, leukemia, or cancers such as colon, breast, gastric, ovarian, cervical, renal, prostate, lymphoma, neuroblastoma, pancreatic and blader cancer.
Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
[0367] It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
[0368] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A"pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term "inhibitorily active metabolite or residue thereof' means that a metabolite or residue thereof is also an inhibitor of a Aurora kinase.
[03691 Pharmaceutically acceptable salts are well known in the art, For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J.
Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1.
4alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quatemization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0370] As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil;
sesame oil;
olive oil; coxn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; cyclodextrin-type compounds such as Captisol ; Ringer's solution;
ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
103711 Uses of Compounds and Pharmaceutically acceptable compositions [0372] Research Uses 103731 According to the present invention, the inventive compounds may be assayed in any of the available assays known in the art.for identifying compounds _ having protease inhibitory activity. For example, the assay may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc.
[0374] In certain exemplary embodiments, compounds of this invention were assayed for their ability to inhibit protein kinases, more specifically Aurora.
[0375] Thus, in one aspect, compounds of this invention which are of particular interest include those which:
= are inhibitors of protein kinases;
= exhibit the ability to inhibit Aurora kinase;
= are useful for treating mammals (e.g., humans) or animals suffering from an Aurora-mediated disease or condition, and for helping to prevent or delay the onset of such a disease/condition;
= exhibit a favorable therapeutic profile (e.g., safety, efficacy, and stability).
[0376] In certain embodiments, compounds of the invention are Aurora kinase inhibitors. In certain exemplary embodiments, inventive compounds are Aurora-A
inhibitors. In certain exemplary embodiments, inventive compounds have cell ICs0 values <100 M. In certain other embodiments, inventive compounds have CellICso values < 75 M. In certain other embodiments, inventive compounds have CellICso values < 50 M. In certain other embodiments, inventive compounds have cellICso values <_ 25 M. In certain other embodiments, inventive compounds have CeIIICso values <_ 10 M. In certain other embodiments, inventive compounds have Ce ICso values <_ 7.5 M. In certain other embodiments, inventive compounds have Ce)IICso values < 5 M. In certain other embodiments, inventive compounds have CellICs0 values <_ 2.5 M. In certain other embodiments, inventive compounds have CeDICso values < 1 M. In certain other embodiments, inventive compounds have CellICso values <_ 800 nM. In certain other embodiments, inventive compounds have CeilICso values < 600 nM. In certain other embodiments, inventive compounds have celtICso values <_ 500 nM. In certain other embodiments, inventive compounds have Cell ICs0 values < 300 nM. In certain other embodiments, inventive compounds have Ce11ICso values < 200 nM. In certain other embodiments, inventive compounds have CellICso values < 100 nM.
[0377] In yet another aspect, a method for the treatment or lessening the severity of an Aurora-mediated disease or condition is provided comprising administering an effective- amount of a compound, or a pharmaceutically acceptable _composition comprising a compound to a subject in need thereof. In certain embodiments of the present invention an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of an Aurora-mediated disease or condition. The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of an Aurora-mediated disease or condition. The exact -amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.
[0378] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
[0379] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
103801 Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[0381) The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
103821 In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The, rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absozption_ of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[0383] Compositions' for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-imtating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[03841 Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[0385] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
[0386] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.

Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[03871 Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[0388] As described generally above, the compounds of the invention are useful as inhibitors of protein kinases. In one embodiment, the compounds and compositions of the invention are Aurora kinase inhibitors, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation of Aurora kinase is implicated in the disease, condition, or disorder. When activation of Aurora kinase is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as "Aurora-mediated disease" or disease symptom. Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of Aurora kinase is implicated in the disease state.

(0389] The activity of a compound utilized in this invention as an Aurora kinase inhibitor, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated Aurora A, B and/or C. Alternate in vitro assays quantitate the ability of the inhibitor to bind to Aurora A, B and/or C. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/Aurora A, B and/or C, complex and detennining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with Aurora A, B
and/or C bound to known radioligands.
[0390] The term "measurably inhibit", as used herein means a measurable change in Aurora A, B and/or C activity between a sample comprising said composition and a Aurora A, B and/or C kinase and an equivalent sample comprising Aurora A, B and/or C kinase in the absence of said composition.
[0391] The term "Aurora-mediated disease" or "Aurora-mediated condition", as used herein, means any disease or other deleterious condition in which Aurora is known to play a role. The terms "Aurora-mediated disease" or "Aurora-mediated condition" also -mean those diseases or conditions that are alleviated by _treatment with an Aurora inhibitor. Such conditions include, without limitation, colon, breast, stomach, and ovarian cancer. The term "Aurora-mediated disease", as used herein, means any disease or other deleterious condition or disease in which Aurora is known to play a role. Such diseases or conditions include, without limitation, cancers such as colon and breast cancer.
[0392] It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".
[0393] For example, other therapies, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of therapies or anticancer agents that may be used in combination with the inventive anticancer agents of the present invention include surgery, radiotherapy (in but a few examples, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile,- Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine,_ Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), GleevecTM, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer therapies see, The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (CNI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs (www.fda.gov/cder/cancer/druglistframe - See Appendix).
[03941 Other examples of agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as Aricept and Excelon ; treatments for Parkinson's Disease such as L-DpPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex and Rebie), Copaxone , and mitoxantrone;
treatments for asthma such as albuterol and Singulair ; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, TL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine;
neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE
inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
[0395] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as_ the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
[0396] The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.

[0397] Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
[0398] Another aspect of the invention relates to inhibiting Aurora A, B
and/or C activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof;
biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
[0399] Inhibition of Aurora A, B and/or C kinase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art.
Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

TREATMENT KIT
[0400] In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aia can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

EQUIVALENTS
[0401) The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should fiuther be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the_art.
[04021 The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and the equivalents thereof.

EXEMPLIFICATION
[0403] The compounds of this invention and their preparation can be understood further by the examples that illustrate some of the processes by which these compounds are prepared or used. It will be appreciated, however, that these examples do not limit the invention. Variations of the invention, now known or fiu ther developed, are considered to fall within the scope of the present invention as described herein and as hereinafter claimed.
[0404] EXAMPLE 1 PhthN- ~ N 1) aq. NaHCO3/DCM PhthN N O CF3 ~~,~ r HBr ~ ~
~NHz F3C ~ NCO S H~N \ ~
2) DCM, II J H
~ ~~õi~1' 2 H2NNH2, EtOH H2N--\ N CF3 a 60 C, 3h ~
H~N ~ /
H

[0405] Compound 2: A mixture of 1 (15.5 g, 44.0 mmol, Eriks, J.C. et al.
J.Med.Chem., 1992, 3239.) in 250 mL aqueous sat. NaHCO3 and 150 mL water was extracted three times with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The residue was dissolved in dichloromethane (500 mL) and carefully treated with 3-trifluoromethylphenyl isocyanate (6.1 mL, 44.3 mmol).
After 3h at room temperature, another 0.50 mL of the isocyanate was added.
After 5 h, the resulting white precipitate was filtered off and washed with dichloromethane to afford 2, ES (+) MS m/e = 461 (M+1).
[0406) Compound 3: The solid (2) obtained in the previous step was taken up in ethanol and treated with hydrazine (8.5 mL). The mixture was heated at for 5 h. After cooling to ambient temperature, the mixture was filtered and concentrated to yield 12.4 g(61 % for 2 steps) of a white solid 3, ES (+) MS
m/e =
331 (M+1).
[0407] EXAMPLE 2 H2N--~ N F
O .~
H~N~~
H

[04081 Compound 4: This compound was made according to procedures towards the synthesis of 2 and 3 except that 3-fluorophenyl isocyanate was used in place of 3-trifluoromethylphenyl isocyanate in the first step in preparation of 2.

[0409] EXAõMPLE 3 pTsOH NH K2CO3, acetone N-NH O MeOH, 65 C N ~ 0 Mel, 70 C _ N-N O*N-N 0 OH OMe '~OMe I\ OMe NOZ NOz NO

104101 Compound 5: p-Toluene sulfonic acid monohydrate (0.3 g , 1.6 mmol) was added to a solution of 4-nitro-3-pyrazole carboxylic acid (5.0 g,31.8 mmol) in 60 mL of methanol. The reaction mixture was heated and stirred overnight at 65 C. After the reaction mixture was cooled to room temperature, saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate (x3). The combined organics were washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford 5 (4.79 g, 88%) as white solid.

NMR (d6-DMSO) S 3.85 (s, 311) 8.81 (s, 1H); ES (+) MS m/e = 172 (M+1).
[0411) Compound 6 and 6A: To a mixture containing 5 (3.1 g, 18.1 mmol) and potassium carbonate (5.0 g, 36.2 mmol) in 60 mL of acetone was added methyl iodide (2.2 mL, 36.2 mmol). The resulting solution was heated and stirred at for 2 hours. After the reaction mixture was cooled to room temperature,-water was added and the mixture was extractred with ethyl acetate (x3). The combined organics were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 20% ethyl acetate in hexanes as the eluent to afford 6 (1.1 g, 33%) as white solid. 'H NMR (d6-DMSO) S 3.96 (s, 3H) 3.98 (s, 3H) 8.36 (s, 1H); ES (+) MS
m/e = 186 (M+1) and using 30% ethyl acetate in hexanes to afford 6A (2.2 g, 66%) as white solid. 'H NMR (d-CDC13) 6 3.98 (s, 3H) 4.00 (s, 3H) 8.13 (s, 1H); ES (+) MS
mie =186 (M+1).
[0412] EXAMPLE 4 NH
N-N p H21Pd/C /
~ MeOH N'N O Me NHz .HOAc N'N OH
NO OMe 9HO DIPEA, n-BuOH
2 NH2 110 C N=/

r N-N Ci SOCI2 DMF 1 / ~N
90bC
N=/

[0413] Compound 7: 10% wt. Pd/C (0.15 g, 0.14 mmol) was added to a solution containing 6 (0.26 g, 1.4 mmol) in 10 mL of methanol. The mixture was stirred under a hydrogen atmosphere at ambient temperature. After 3 hours, the reaction mixture was filtered thru a plug of Celite. The resulting filtrate was concentrated under reduced pressure to afford 7 (0.20 g, 91%), ES (+) MS m/e =

(M+1).
[0414] Compound 8: To a solution of 7 (0.92 g, 5.9 mmol) in 5 mL of Hunig's base and 5 mL of n-butanol was added formamidine acetate (0.68 g, 6.5 mmol). The reaction mixture was heated and stirred at 110 C for 1 hour. After cooling to room temperature, the white precipitate was collected by filtration and washed with diethyl ether. The resulting white precipitate was dried under reduced pressure to afford 8 (0.83g, 94%). 1H NMR (d6-DMSO) S 4.33 (s, 3H) 8.50 (s, 1H) 8.80 (s, 1H); ES (+) MS m/e = 151 (M+1).
[0415] Compound 9: To a solution of 8 (0.835 g, 5.5 mmol) in 10 mL
thionyl chloride was added 0.5 mL DMF. The resulting mixture was heated to 90 C
under nitrogen for 1 hour. After cooling to room temperature, the solvents were removed under reduced pressure. Water was added to the resulting residue and the mixture was extracted with dichloromethane (x3). The combined organics were dried (MgSO4) and concentrated under reduced pressure to afford 9(0.94 g, 100%), ES (+)MSm/e=169(M+1).
[0416] EXAMPLE 5 'N O H2, Pd/C NH
N-N o I~ ~N-N OH
lOMe MeOH NH2.HOAc N
NO2 OMe DIPEA, n-BuOH N
NH2 110oC N

N-N CI

N
SO 90d DMF N---/

[0417] Compound 7A: This compound was made according to procedures towards the synthesis of 7, except that 6A was used in place of 6, ES (+) MS
m/e =
156 (M+1).
[0418] Compound 8A: This compound was made according to procedures towards the synthesis of 8, except that 7A was used in place of 7, ES (+) MS
m/e =
151 (M+1).
[0419] Compound 9A: This compound was made according to procedures towards the synthesis of 9, except that 8A was used in place of 8, ES (+) MS
m/e =
169 (M+1).
[0420] EXAMPLE 6 F F
F ~

N_ / C~ DIPEA, DMF ONH

I
NH
N ~--,S1 N=-/ N-N HN ~~N

N=-J

[0421] Compound 10: To a solution of 3 (0.33g, 1.0 mmol) and Hunig's base (0.52 mL, 3.0 mmol) in 3 mL of DMF was added 9 (0.169 g, 1.0 mmol). The resulting mixture was heated and stirred at 90 C for 1 hour. After the reaction was cooled to room temperature, water was added and washed with ethyl acetate (x3).
The combined organics were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by prep RP-HPLC. The 'fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 10 (59 mg, 9%) as the bis TFA salt. 'H NMR (d6-DMSO) S 3.10 - 3.13 (m, 2H) 3.90 - 3.92 (m, 2H) 4.33 (s, 3H) 7.19 (s, IH) 7.36 (m, IH) 7.51 - 7.55 (m, 1H) 7.62 - 7.64 (m, 1H) 8.01 (s, 1 H) 8.16 (s, IH) 8.72 (s, 1 H) 9.02 (bs, 1H) 9.57 (s, 1 H); ES (+) MS m/e = 463 (M+1).
[04221 EXAMPLE 7 F F

3 N-N CI DIPEA, DMF O''~,NH
90 C '( NH
N ---{ S
N'J N'N HN--/ ~'--N

'N 99 N-=/

[0423] Compound 11: This compound was made according to procedures towards the synthesis of 10, except that 9A was used in place of 9, ES (+) MS
m/e =
463 (M+1).
[0424] EXAMPLE 8 PhthN-\
,,-N Boc20, Et3N PhthN--\ N
~~~ j) HBr ~~ 1!
NH2 DMAP, MeCN, 66 C NHBoc H2NNH2, THF H2N-~ ,.~N
Reflux 13 S' NHBoc [0425] Compound 12: 1 (60g, 170 mmol) was slurried in 190 ml acetonitrile.
DMAP (.05 eq, lg) and Et3N (1.1 eq, 26 ml) were added, turning the reaction yellow, forming more precipitate and raising the reaction temperature to 31 C.
Boc20 (1.2 eq, 44g) was added and the reaction heated to reflux at 66 C. As the temperature rose, the thick reaction mixture became easier to stir. After 45 min, the yellow color had disappeared and the reaction was done by TLC (50/50 EtOAc/hexane.) The reaction was cooled to 0 C, the solid collected via filtration and washed with cold ACN. The solid was then slurried with water, collected via filtration. Drying in vacuo gave 55g white solid (86% yield.).
[0426] Compound 13: 12 (40g, 107 mmol) were slurried in 500 ml THF and heated to reflux, dissolving almost all of the phthalimide. Anhydrous hydrazine (2 eq., 6.7 ml) was added and the reaction stirred 2hr at which time TLC (50/50 EtOAc/hexane) showed the reaction to be -75% complete. 1 eq. hydrazine was added and after 1 more hr at reflux the reaction was complete by TLC. The reaction was cooled to 40 C and the white precipitate was filtered off and washed with ml THF. The filtrate was concentrated in vacuo to -200 ml at which time a little white solid forms. The mixture was diluted with 200 ml hexane, giving a milky solution, and let stand overnight. The solid was removed via filtration (4g of 1:1 product: phthalic hydrazide) and the filtrate concentrated in vacuo to give 23g white solid (88% yield.).
[0427] EXAMPLE 9 -C-NH KZC03, acetone N-NH O Mel, 70 C N-N 0 N'N 0 / +
YOMe OMe OMe NOz NO2 NO2 [042S] Compound 14 and 14A: To a mixture of 5 (1.9 g, 11.1 mmol) and potassium carbonate (3.07 g, 22.2 mmol) in 100 mL of acetone was added iodoethane (3.46 g, 22.2 mmol). The reaction was heated and stirred for 2 hours at 70 C. After cooling to room temperature, the mixture was diluted with water extracted with ethyl acetate (x2). The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using 20% ethyl acetate in hexanes to afford (0.65 g, 29%). 'H NMR (d6-DMSO) 8 1.37 (t, 3H, T= 7.3 Hz) 3.97 (s, 3H) 4.28 (q, 2H, J= 7.3 Hz) 8.39 (s, 1H); ES (+) MS m/e = 200 (M+1) and using 30% ethyl acetate in hexanes to afford 14A (1.3 g, 58%). 'H NMR (d6-DMSO) S 1.40 (t, 3H, J
= 7.3 Hz) 3.87 (s, 3H) 4.22 (q, 2H, J = 7.3 Hz) 9.00 (s, 1H); ES (+) MS m/e =

(M+1) [0429] EXAMPLE 10 NH
N"'N O -N ~
1 H2, Pd/C N O NH2HOAc NN OH
OMe MeOHr f~
NO e DIPEA, n-BuOH

SOCI9, DMF N-N CI
9o C 1 f ~N
N=~

[0430] Compound 15: 10% wt. Pd/C (0,35 g, 0.33 mmol) was added to a solution containing 14 (0.65 g, 3.3 mmol) in 30 mL of methanol. Atmospheric hydrogen pressure was introduced via balloon. After stirring for 3 hours, the reaction mixture was filtered thru a plug of Celite. The resulting filtrate was concentrated under reduced pressure to afford 15 (0.55 g, 100%), ES (+) MS m/e =
170 (M+1).
[0431] Compound 16: Formamidine acetate (0.37 g, 3.6 mmol) was added to a solution of 15 (0.55 g, 3.3 mmol) in 5 mL of Hunig's base and 5 mL of n-butanol.
The reaction mixture was heated and stirred at 110 C for 1 hour. After the reaction mixture was cooled; brine water was added and washed with ethyl acetate (x3).
The combined organics were dried with MgSO4, filtered, and concentrated to afford (0.51 g, 97%). ES (+) MS m/e =165 (M+1).
[0432] Compound 17: 0.2 mL of DMF was added to a solution containing 16 (0.51 g, 3.1 mmol) in 6 mL of thionyl chloride. The reaction mixture was heated to 90 C for 1 hour. After the reaction mixture was cooled to room temperature, the solvents were removed under reduced pressure. Water was added to the resulting residue and extracted with dichloromethane (x3). The combined organics were dried with MgSO4, filtered and concentrated to afford 17 (0.57 g, 100%), ES
(+) MS
m/e = 183 (M+1).
[0433] EXAMPLE 11 N -N O NH N-N OH
Y-/<Ome H2, Pd/C N'N O ~'NH2.HOAc MeUH~ ~
N
OMe DIPEA, n-BuOH N_/

SOCI, DMF NyN CI
90bC _ N
N=/17A

[04341 Compound 15A: This compound was made according to procedures towards the synthesis of 15, except that 14A was used in place of 14, ES (+) MS rn/e = 170 (M+1).
[0435] Compound 16A: This compound was made according to procedures towards the synthesis of 16, except that 15A was used in place of 15, ES (+) MS m/e =165 (M+l). [0436] Compound 17A: This compound was made according to procedures towards the synthesis of 17, except that 16A was used in place of 16, ES (+) MS rn/e = 183 (M+1).
[0437] EXAMPLE 12 Boc N'N CI 13 SYNH

/ \N DIPEA, DMF N-N HN--~ ~'--N
N 90 C Y/- \11 17 N=/ 18 HCI \ NH2 OCN ~cr CI
MeOH
N N HN_N
I
3HCI Et3N, THF

CI Q
O~Y NH
NH
_/
N..N HN
I ~
N=~

[0438] Compound 18: To a solution containing 13 (0.75g, 3.1 mmol) "and Hunig's base (1.6 mL, 9.3 mmol) in 3 mL of DMF was added 17 (0.57 g, 3.1 mmol).
The resulting mixture was heated and stirred at 90 C for I hour. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (x3). The combined organics were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using 10% MeOH in DCM to afford 18 ( 0.726 g, 60%). ES (+) MS m/e = 390 (M+1).
[0439] Compound 19: To a solution of 18 (0.73 g, 1.9 mmol) in I mL MeOH
was added 5 mL of 4.OM HCI in dioxanes. The reaction mixture was stirred for 1 hour then concentrated under reduced pressure to afford 19 (0.74 g, 100%). ES
(+) MS m/e = 290 (M+1).
[0440] Compound 20: 3-chlorophenyl isocyanate (64 mgs, 0.42 mmol) was added to a solution containing 19 (80 mgs, 0.21 mmol) and triethylamine (0.14 mL, 1.0 mmol) in 3 mL of THF. The reaction mixture was stirred for 30 minutes, concentrated, and purified by prep RP-HPLC to afford 20. 'H NMR (d6-DMSO) 8 1.32 - 1.36 (t, 3H, J= 6.8 Hz) 3.12 - 3.15 (m, 2H) 3.92 - 3.93 (m, 2H) 4.67 -4.72 (q, 2H, J= 7.4 Hz) 7,06 (bs, IH) 7.15 (s, 1H) 7.30 - 7.32 (m, 1H) 7.70 (s, 1H) 8.21 (s, 1H) 8.74 (s, 1H) 8.91 (bs, 1H) 9.37 (s, 1H); ES (+) MS m/e = 443 (M+1).
[0441] EX.A,.MPLE 13 F3C q N-N HN-/ ~'-N NH
yl--~)N N
N
N= / 19 3HCI Et3N, THF N.-N HN~
N

4/\
N-=1 [0442] Compound 21: 3-trifluorophenyl isocyanate (77 mgs, 0.42 mmol) was added to a solution containing 19 (0.21 mmol, 80 mgs) and triethylamine (0.14 mL, 1.0 mmol) in 3 mL of THF. The reaction mixture was stirred for 30 minutes, concentrated, and purified by prep RP-HPLC to afford 21. 'H NMR (d6-DMSO) 8 1.32 - 1.35 (t, 3H, 3= 7.4 Hz) 3.12 - 3.15 (m, 2H) 3.92 - 3.93 (m, 2H) 4.67 - 4.72 (q, 2H, J= 7.4 Hz) 7.16 (bs, 1H) 7.34 - 7.36 (in, 1H) 7.50 - 7.52 (m, IH) 7.61 - 7.63 (m, IH) 8.02 (s, 1H) 8.21 (s, 1H) 8.74 (s, 1H) 8.91 (bs, 1H) 9.55 (s, 1 H); ES (+) MS .m/e = 477 (M+1).
[0443] EXAMPLE 14 ~
\ ~NH2 SYN ~ f CF3 N N HNN Et3N, THF ..N HN_./ 'N O
N N
N_/ 3HCI -~ I / \N
19 Cl ~ CF3 Nu/ 22 O

[0444] Compound 22: To a mixture of 19 (0.072 g, 0.1 S mmol) and triethylamine (0.13 mL, 0.9 mmol) in 3 mL of THF was added 3-(trifluoromethyl)-benzoyl chloride (0.038 g, 0.18 mmol). After stirring for 0.5h, the reaction was quenched with methanol and concentrated under reduced pressure to yield an oily residue. The crude was purified by prep RP-HPLC to afford 22. ES (+) MS rn/e =
462 (M+1).
[0445] EXAMPLE 15 ~--~gYNH$ HAi'U, Et3N N~N
N~~" HN/ \-N DCM < H

N 3HCI HO2C CF3 N~N S}-NH

[0446] Compound 23: HATU (0.085 g, 0.22 mmol) was added to a solution containing trifluoro-m-tolyl acetic acid (0.046 g, 0.22 mmol), 19 (0.089 g, 0.22 mmol) and triethylamine (0.16 mL, 1.1 mmol) in 3 mL of DCM. The reaction mixture was stirred for 30 minutes and quenched with methanol. The reaction mixture was then concentrated under reduced pressure resulting in an oily residue.
The crude was purified by prep HPLC to afford 23. ES (+) MS m/e = 476 (M+1).
[0447] EXAMPLE 16 1.) DIPEA, DMSO

S NH2 NN~
~
N ~ N
N HN--// N
/ \N 2.) HpN ~ CF3 N ~ 3HCI ~

3.) DCC, 100 C
SYN~N

HN ~ ~ CF3 NN HN
I
N
N-= 24 [04481 Compound 24: 1,1'-thiocarbonyldiimidazole (0.054 g, 0.3 mmol) was added to a solution containing 19 (0.12g, 0.3 mmol) and Hunig's base (0,2 mL, 1.2 mmol) in 3 mL of DMSO. The reaction mixture was heated at 60 C.
After 30 minutes, 4-(trifluoromethyl)-o-phenylenediamine (0.053 g, 0.3 mmol) was added. The reaction mixture continued to be stirred and heated at 60 C
overnight.
DCC (0.062 g, 0.33 mmol) was added and the reaction was heated to 100 C. After I
hour, the reaction mixture was cooled to room temperature. Water was added and the heterogeneous solution was stirred for 15 minutes. The dark brown precipitate was collected and purified by prep RP-HPLC to afford 24. ES (+) MS m/e = 474 (M+1).

Boc2O BQc, H2, Pd/C
N-NH Et3N, THF N-N MeOH
I ~ CO2Me ~~ COzMe Boc, NH
N-N ~ N-NH OH SOCI2 I/,N DMF, 90 C
C
CO2Me NH2.HOAc NH2 26 DIPEA, n-BuOH, 110 C N"/ 27 N-NH CI
I / N
N-=J 28 [0450] Compound 25: BocaO (12.75 g, 58.4 mmol) was added to a solution containing 5 (10.0 g, 58.4 mmol) and Et3N (8.1 mL, 58.4 mmol) in THF (200 mL).
The reaction mixture was stirred at room temperature for 1 hour and was then diluted with water. The aqueous layer was extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and concentrated to afford 25 (14.7 g, 93%), ES(+) MS m/e = 272 (M+1)..
104511 Compound 26: 10%wt Pd/C (2.88 g, 2.7 mmol) was added to a solution containing 25 (14.7 g, 54.2 mmol) in MeOH (200mL). The reaction mixture was stirred under 1 atm H2 pressure for 4 hours. The mixture was then filtered thru a plug of Celite and concentrated to afford 26 (11.1 g, 85%), ES
(+) MS
m/e = 242 (M+1).
[0452] Compound 27: Formamidine acetate (40.3 mmol, 4.2 g) was added to a solution containing 26 (8.85 g, 36.7 mmol) in Hunig's base (40 mL) and n-BuOH
(40mL). The stirred solution was heated at 110 C for 1 hour. After cooling to ambient temperature the resulting solid was collected, washed with dichloromethane, and dried under reduced pressure to afford 27 (4.46 g, 89%), ES
(+) MS m/e = 137.
[0453] Compund 28: DMF (1.05 mL) was added to a solution containing 27 (1.0 g, 7.3 mmol) in thionyl chloride (21 mL). Heated the stirring solution to for 1 hour. Cooled the homogeneous reaction mixture to room temperature.
Concentrated to remove volatiles and diluted the reaction mixture with EtOAc followed by ice. Extracted the aqueous layer with EtOAc. Combined the organics, washed with saturated NaHCO3, dried with MgSO4, filtered and concentrated to afford 28 (0.73 g, 64%), ES (+) MS m/e =155.
[04541 EXAMPLE 18 I~ NHz CI V130 N \ I
~
BocHN I / O
29 7HF, NEt3 BocHN

N-N CI

~ ~ N '~7 N~ N N HN ~~ NH ~/
N
HZN '~ 0 DIoEA, DMF I ~N 33 HCI

[0455] Compound 31: Add 30 (1.0 mmol) drop-wise to a solution of 29 (1.0 mmol) and NEt3 (2.0 mmol) in THF 10.0 mL under nitrogen at 0 C. When the reaction is completed, dilute with ethyl acetate. Wash with 1.0 M HCI, aqueous sat.
NaHCO3, and brine. Dry with Na2SO4, concentrate, and purify by flash column chromatography to obtain 31.

[04561 Compound 32: Stir a mixture of 31 (0.5 mmol) in 4.OM HC1 in dioxane.
After completion, concentrate the mixture and dry the residue under high-vacuum to afford 32.
[0457] Compound 33: Add 17 (1.0 mmol) to a solution containing 32 (1.0 mmol), Hunig's base (2.0 mmol) in 10 mL of DMF. Heat the stirring solution to 90 C for 1 hour. Cool the reaction mixture to room temperature and dilute with water. Extract the aqueous layer with ethyl acetate (x3). Combine organics, dry with MgSO4, filter, and concentrate to obtain crude residue. Purify using prep. RP-HPLC to afford 33.
[0458] EXAMPLE 19 N hydrazine N EtOH, 80 C H2N N Boc20, Et3N
k ' -~- ~ THF, H20 H-Br H-Br 34 ~ Boc, Boc, HN
/ ~' N 0 HN N OCN Ci S~ ~ ~ I
~ , C' ~i g~NH2 Et3N, THF N H

O a dioxanes H-CI N N Ci [0459] Compound 34: Hydrazine monohydrate (8.4 mL, 173.6 mmol) was added to a heterogeneous solution of 1 (15.37 g, 43.4 mmol, Eriks, J.C. et al.
.I.Med.Chem., 1992, 3239.) in THF (150mL) and EtOH (150mL). The reaction mixture was stirred and heated to 80 C for 5 hours. The reaction mixture was cooled to room temperature and filtered. The resulting white solid was washed with methanol. The filtrate was then concentrated to obtain 34 (9.72 g, 100%) as a white solid, ES (+) MS m/e = 144 (M+1).
[0460] Compound 35: Boc20 (10.4 g, 47.7 mmol) was added to a solution of 34 (9.72 g, 43.4 mmol) in Et3N (12.1 mL, 86.7 mmol), THF (220 mL) and H20 (20 niL). The reaction mixture was stirred for 1 hour and was then diluted with water/EtOAc (1:1, 600 mL). The layers were separated and the aqueous layer was extracted with EtOAc (150mL x 2). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to afford 35 (10.55 g, 100%) as a white solid, ES (+) MS m/e = 244 (M+1).
[0461] Compound 36: 3-Chlorophenyl isocyanate (5.2 mL, 43.3 mmol) was added to a solution of 35 (10.55 g, 43.3 mmol), Et3N (12.7 mL, 91.0 mmol), and THF (220mL). The reaction mixture was stirred for 3 hours and concentrated under reduced pressure. The resulting solid was triturated with 1:1 DCM: hexanes to afford 36 (16g, 93%) as a white solid, ES (+) MS m/e = 397 (M+1).
[04621 Compound 37: HCl (50 mL, 4M in dioxanes) was added to a solution of 36 (16 g, 40.3 mmol) in MeOH (200 niL). The reaction mixture was stirred for I
hour and concentrated to afford 37 (13.43 g, 100%) as a white solid, ES (+) MS
m/e = 297 (M+1).
[0463] EXAMPLE 20 aci CN Boc, / CN
HN N Q
~
1) H2N
tri hos ene CH CN 75 C ~ ~ I
35 p g ~ 3 ~ H H ci 2) Et3N, CH3CN

HCI
N
dioxanes H2N--~ N o C
~
H-Cl S H H Ci [0464] Compaund 38: Triphosgene (0.48 g, 1.61 mmol) was added to a solution of 4-amino-2-chlorobenzonitrile (0.62g, 4.1 mmol) in CH3CN (10mL).
The reaction mixture was heated to 75 C for 1.5 hours and then slowly cooled to room temperature. A solution containing 35 (0.99 g, 4.1 mmol), Et3N (2.2 mL, 16.3 mmol) and CH3CN (lOmL) was added and stirred for 15 minutes. The reaction mixture was diluted with HZO and extracted with EtOAc. The combined organics were dried with MgSO4, filtered, concentrated and purified by column chromatography on silica gel using 20% MeOH in DCM to afford 6(0.43 g, 30%).
[04651 Compound 39: HCl (2 mL, 4M in dioxanes) was added to a solution of 38 (0.43 g, 1.0 mmol) in MeOH (5 mL). The reaction mixture was stirred for hour and concentrated to afford 39 (0.37 g, 100%) as a white solid, ES (+) MS
m/e =
322 (IvI+1).
]0466] EXAMPLE 21 H2N--~ ~ 0 / I CN
S lk ' 104671 Compound 39A: This compound was made according to procedures towards the synthesis of 38 and 39 except that 4-amino-2-trifluoromethylbenzonitrile was used in place of 4-amino-2-chlorobenzonitrile, ES
(+) MS m/e = 356 (M+1).
[0468] EXAMPLE 22 1.) KI, Et3N
H 2-chioroethanot O DMF, 90 C
O ,"~CI 2.) MeOH
'N CO2H pTsOH.H20, 115 C eNO2 HO HO
formamidine acetate O H2, Pd/C ' 0 DIPEA, nBuOH, 110 C
N,N f O MeOH
N N + N J O
~ ~

HO CI
SOCt2 ~
OH DMF, 90 C CI
N ~N ,N N ~N
N~ ~ N J N J

[0469] Compound 40: pTsOH monohydrate (1.2 g, 6.4 mmol) was added to a solution containing 4-nitro-3-pyrazole carboxylic acid (10 g, 63.7 mmol) in 2-chloroethanol (64 mL). The reaction mixture was heated to 11 5 C for 2 hours and cooled to room temperature. The bulk solvent was removed under reduced pressure.
The residue was diluted with EtOAc and aqueous saturated NaHCO3. The layers were separated and the aqueous phase was extractred with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to afford 40 (14 g, 100%), ES (+) MS m/e = 220 (M+1).
[0470] Compound 41: Et3N (18 mL, 127.5 mmol) was added to a solution of 40 (14 g, 63.8 mmol) and KI (1.0 g, 6.4 mmol) in DMF (200 mL). The reaction mixture was heated to 90 C and stirred for 16 hours. Methanol (100 mL) was added and stirred at 90 C for 1 hour. The reaction mixture was cooled to room temperature. Excess methanol was removed under reduced pressure. The reaction mixture was diluted with H20. The aqueous layer was extracted with EtOAc, the combined organics were dried with MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel using 50% EtOAc in hexanes to afford 41 (6.08 g, 44%), ES (+) MS m/e = 216 (M+1).

[0471] Compound 42: 41 (6.0 g, 27.9 mmol) was placed in a flask containing 10%wt Pd/C (1.48 g, 1.4 mmol) in MeOH (100mL) with 1 atm H2, via balloon.
After stirring overnight, the reaction mixture was filtered thru a plug of Celite and concentrated to afford 42 (5.16 g, 100%), ES (+) MS m/e = 186 (M+1).
[0472] Compound 43: Forrnamidine acetate (3.34 g, 30.7 mmol) was added to a solution containing 42 (5.16 g, 27.9 mmol), Hunig's base (30 mL) and n-butanol (30 mL). The reaction mixture was heated to 110 C for 1 hour. The reaction mixture was cooled to room temperature. EtzO (30 mL) was added and the resulting solid was collected, washed with EtZO, and dried under vacuum to afford 43 (4.3g, 85%), ES (+) MS m/e = 181 (M+l).
[0473] Compound 44: DMF (8mL) was added to a solution containing 43 (4.32 g, 24.0 mmol) in SOC12 (80 mL). The heterogeneous reaction mixture was heated to 90 C for 30 minutes and the homogeneous solution was cooled to room temperature. The solvents were removed under reduced pressure. The resulting residue was diluted with EtOAc, followed by ice. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with saturated NaHCO3, followed by brine. The resulting organics were dried with MgSOa, filtered, and concentrated to afford 44 (3.02 g, 58%), ES (+) MS m/e =

(M+1).
[0474], EXAMPLE 23 N CO2Me Et0z ~
NN jCOMe_NaH, DMF, 75 C -N' ~ C N C02Me N02 Et02C NOZ + \ ~
SrCO2Et NO2 1) H2, Pd/C
MeOH
2) formamidine acetate DIPEA, nBuOH, 110 C
OH
N ' ~ N EtO2C--\ OH
Et02C

SOCIZ
DMF, 90 C
CI
tN' N Et02C-\ Cf N N
Et02C N - \ ~
j N ~
N

[0475] Compound 45 and 45A: Ethyl bromoacetate (3.9 mL, 35.0 mmol) was added to a preheated solution of 5 (4.0 g, 23.4 mmol) and 60% wt of NaH (1.4 g, 35.0 mmol) in DMF (50 mL) at 75 C. The reaction mixture was stirred for 30 minutes and then cooled to room temperature. The reaction mixture was diluted with H20. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel using 20% EtOAc in hexanes to afford 45A (0.79 g, 13%), ES (+) MS m/e = 258 (M+1) and using 30% EtOAc in hexanes to afford 45 (3.3 g, 55%), ES (+) MS in/e = 258 (M+1).

[0476] Compound 46: 45 (6.12 g, 23.8 mmol) was placed in a flask containing 10%wt Pd/C (1.27 g, 1.2 mmol) in MeOH (30mL) with I atm H2, via balloon. The reaction was stirred overnight. Filtered thru a plug of Celite and concentrated to afford oily residue. The residue was diluted with n-butanol (50 mL) followed by Hunig's base (50 mL). Formamidine acetate (2.72 g, 26.2 mmol) was added and the reaction was heated to 110 C for 1 hour. The reaction was cooled to room temperature and concentrated to remove solvents. The resulting residue was diluted with H20. The aqueous layer was extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to afford 46 (3.86 g, 73%), ES (+) MS m/e = 223 (M+1).
[0477] Compound 46A: 45A (0.79 g, 3.1 mmol) was placed in a flask containing 10%wt Pd/C (0.32 g, 0.3 mmol) in MeOH (30mL) with I atm H2, via balloon. The reaction was stirred overnight. Filtered thru a plug of Celite and concentrated to afford oily residue. The residue was diluted with n-butanol (6 mL) followed by Hunig's base (6 mL). Formamidine acetate (0.33 g, 3.1 mmol) was added and the reaction was heated to 110 C for 1 hour. The =reaction was cooled to room temperature and concentrated to remove solvents. The resulting residue was diluted with H20. The aqueous layer was extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to afford 46A (0.63 g, 95%), ES (+) MS m/e = 223 (M+1).
[0478] Compound 47: DMF (2.5 mL) was added to a solution containing 46 (1.69 g, 7.6 mmol) in SOCl2 (25 mL). The heterogeneous reaction mixture was heated to 90 C for 30 minutes and the homogeneous solution was cooled to room temperature. The solvents were removed under reduced pressure. The resulting residue was diluted with EtOAc, followed by ice. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with saturated NaHCO3, followed by brine. The resulting organics were dried with MgSO4, filtered, and concentrated to afford 47 (1.56 g, 92%), ES (+) MS m/e =

(M+1).
[0479] Compound 47A: DMF (1.0 mL) was added to a solution containing 46A (0.63 g, 2.8 mmol) in SOC12 (10 mL). The heterogeneous reaction mixture was heated to 90 C for 30 minutes and the homogeneous solution was cooled to room temperature. The solvents were removed under reduced pressure. The resulting residue was diluted with EtOAc, followed by ice. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with saturated NaHCO3i followed by brine. The resulting organics were dried with MgSO4, filtered, and concentrated to afford The resulting organics were dried with MgSOa, filtered, and concentrated to afford 18 (0.52 g, 76%), ES
(+) MS m/e = 241 (M+1).
[0480] EXAMPLE 24 CI
CI
N ~N
H2N N C / CN N~ I NJ

S~ H J1 H~ I
CI
H-Cl DIPEA,DMF

CN
0cl ~ NaN3, KI
CI I N NH DIPEA
HN" ~'" _S~NH DMF, 90 C
N N I ~N 48 N ~ J 07cl C
Me3P
N3 h ~ ~-NH NH THF, H20 HN" S
N
N~ NJ 49 CN
CI
OL ~
H2N ~ N ~'-NH
~ NH
HN" v 'S
N N

[0481] Compound 48: 39 (3.07 g, 8.6 mmol) was added to a solution containing 44 (1.86 g, 8.6 mmol) and Hunig's base (5.9 mL, 34.3 mmol) in DMF

(30 mL). The reaction mixture was heated to 90 C and stirred for 1 hour. The reaction was cooled to room temperature. The reaction was diluted with H20 and extracted aqueous layer with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated. Purification on silica gel using 10% MeOH
in DCM afforded 48 (1.78 g, 41%), ES (+) MS m/e = 503 (M+1).
[0482] Compound 49: Sodium azide (0.15 g, 2.4 mmol) was added to a solution containing 48 (0.6 g, 1.2 mmol), KI (0.02 g, 0.1 mmol), and Hunig's base (0.64 mL, 3.6 mmol) in DMF (5 mL). The reaction mixture was heated to 90 C and stirred for 1 hour. The reaction mixture was cooled to room temperature. The reaction was diluted with H20 and extracted aqueous layer with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated.
Purification on silica gel using 10% MeOH in DCM afforded 49 (0.33 g, 54%), ES (+) MS m/e =
510 (M+1).
[04831 Compound 50: Trimethylphosphine (1.3 mL, 1.OM in THF) was added to a solution containing 49 (0.33g, 0.6 mmol) in THF (5mL) and H20 (0.5mL). The reaction mixture was stirred overnight. The reaction mixture was concentrated and triturated with DCM and hexanes to afford 50 (0.31 g, 100%), ES
(+) MS m/e = 484 (M+1).
[0484] EXAMPLE 25 C!

CI
\N 'N
H2N~N O N I N) S-~ 'k ~

DIPEA,DMF

/ ~ Cl O\\
CI ~ ~N~'--NH
HN" ''~ 'S
~
N ~N
N~ I NJ

[04851 Compound 51: 37 (0.35 g, 1.6 mmol) was added to a solution containing 44 (0.54 g, 1.6 mmol) and Hunig's base (1.1 mL, 6.4 mmol) in DMF
(16 mL). The reaction mixture was heated to 90 C and stirred for 1 hour. The reaction was cooled to room temperature. The reaction was diluted with H20 and extracted aqueous layer with EtOAc. The combined organics were dried with MgSOa., filtered, and concentrated. Purification on silica gel using 10% MeOH in DCM
afforded 51 (0.41 g, 54%), ES (+) MS m/e = 478 (M+1).
[04861 EXAMPLE 26 O ct Amine, KI O DIPEA, DMF R ~ ~ NH NH

HNS/' 51 ~
N ~N
N~ NJ

OH
OH
R r CN N
~ ~ - - ~ - -- _ - . ~

OH
HO s N~

"'ON= +' N 6N
. , [0487] Compound 52A: Pyrrolidine (16 mgs, 0.02 mmol) was added to a solution containing 51 (55 mgs, 0.01 mmol), Hunig's base (0.05 mL, 0.3 mmol), and KI (2 mgs) in DMF (3 mL). The reaction mixture was heated to 90 C overnight.
The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 52A as the tris TFA salt, ES (+) MS m/e = 513 (M+1).
[0488] Compound 52B: This compound was made according to procedures towards the synthesis of 52A except that S(+)-3-pyrrolidinol was used in place of pyrrolidine, ES (+) MS m/e = 528 (M+1).
[0489] Compound 52C: This compound was made according to procedures towards the synthesis of 52A except that 3-hydroxypiperidine was used in place of pyrrolidine, ES (+) MS m/e = 542 (M+1).
[0490] Compound 52D: This compound was made according to procedures towards the synthesis of 52A except that 3-hydroxyazetidine was used in place of pyrrolidine, ES (+) MS m/e = 514 (M+1).
[0491] Compound 52E: This compound was made according to procedures towards the synthesis of 52A except that 4-methylpiperazine was used in place of pyrrolidine, ES (+) MS m/e = 541 (M+1).
[0492] Compound 52F: This compound was made according to procedures towards the synthesis of 52A except that 4-hydroxypiperidine was used in place of pyrrolidine, ES (+) MS m/e = 542 (M+1).
[0493] EXAMPLE 27 p ~ CI
RS"Na+ S/ X\J-NH
51 ~ HNS mCPBA
N ~N
N~ I NJ 53 0 O-Cl O O-Cl 0~~S/ N ~NH o. N
HN' S~NH C~S I ~~,_ NH NH
+ HN' S/-' ~
N N
N ,~ N N
54A N~ ~ J 54B

[0494] Compound 53: Sodium thiomethoxide (57 mgs, 0.81 mmol) was added to a solution containing 51(0.31 g, 0.65 mmol) in DMF (3 mL). The reaction mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and purified by column chromatography on silica gel using 10% MeOH in DCM to afford 53 (0.21 g, 66%), ES (+) MS m/e = 489 (M+1).
[0495] Compound 54A and 54B: 77%wt of mCPBA (0.13 g, 0.74 mmol) was added to a solution containing 51 (0.26 g, 0.53 mmol) in DCM. The reaction mixture was stirred overnight. Diluted reaction mixture with saturated NaHC03 and extracted aqueous layer with EtOAc. The combined organics were dried, filtered, and concentrated. . The crude residue was purified by prep RP-HPLC. The fractions containing pure compounds were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 54A as the bis TFA salt, ES (+) MS m/e = 505 (M+1) and 54B as the bis TFA salt, ES (+) MS m/e = 521 (M+1).
[0496] EXAMPLE 28 CN

Amine, KI R ~-' N ~--NH
0 DIPEA, DMF ~NH
~ HN/ \S

N

QQQ' R = 55A 55B 55C
[0497] Compound 55A: Pyrrolidine (0.033 mL, 0.4 mmol) was added to a solution containing 48 (0.1 g, 0.2 mmol), Hunig's base (0.1 mL, 0.6 mmol) and KI
(3 mgs) in DMF (3 mL). The reaction mixture was heated to 90 C overnight. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 55A as the tris TFA salt, ES
(+) MS m/e = 538 (M+1).
[0498] Compound 55B: Piperidine (0.04 mL, 0.4 mmol) was added to a solution containing 48 (0.1 g, 0.2 mmol), Hunig's base (0.1 mL, 0.6 mmol) and KI
(3 mgs) in DMF (3 mL). The reaction mixture was heated to 90 C overnight. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 55B as the tris TFA salt, ES
(+) MS m/e = 552 (M+1).
[0499] Compound 55C: Morpholine (0.035 mL, 0.4 mmol) was added to a solution containing 48 (0.1 g, 0.2 mmol), Hunig's base (0.1 mL, 0.6 mmol) and KI
(3 mgs) in DMF (3 mL). The reaction mixture was heated to 90 C overnight. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 55C as the tris TFA salt, ES
(+) MS m/e = 554 (M+1).
[0500] EXAMPLE 29 ci 37 o / \ a N N~ ~ N DIPEA, DMF ~ NH NH
Et02C N= 900C HNS
1V,, 47 ~--N ~- ~ 56 Et02C N

[0501] Compound 56t 37 (1.44 g, 4.2 mmol) was added to a solution containing 47 (1.04 g, 4.2 mmol) and Hunig's base (2.2 mL, 13.0 mmol) in DMF
(10 mL). The reaction mixture was heated to 90 C for 1 hour. The reaction was cooled to room temperature. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organics were dried (MgSO4) and concentrated. The crude residue was purified by column chromatography on silica gel using 10% MeOH in DCM to afford 56 (1.0 g, 46%), ES (+) MS m/e = 502 (M+1).
[0502] EXAMPLE 30 c i O
37 O ~NH
Et02C1 CI N
DIpFA, DMF ~ ~-NH
N ~ N 90 C EtO2C~ HN S
N~ ~ NJ N N

47A N~ I N57 [0503] Compound 57: 37 (0.72 g, 2.1 mmol) was added to a solution containing 47A (0.52 g, 2.1 mmol) and Hunig's base (1.1 mL, 6.5 mmol) in DMF
(3 mL). The reaction mixture was heated to 90 C for 1 hour. The reaction was cooled to room temperature. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organics were dried (MgSO4) and concentrated. The crude residue was purified by column chromatography on silica gel using 10% MeOH in DCM to afford 57 (0.3 g, 28%j, ES (+) MS m/e = 502 (M+1).
[0504] EXAMPLE 31 0 O-Cl NaBH4 ~ N NH
THF, MeOH HN~S~NH

IV~ ~N
HO~N ~ N~ 58 105051. Compound 58: Sodium borohydride (8 mgs, 0.2 mm.ol) to a solution containing 56 (0.05 g, 0.1 mmol) in THF (3 mL) and MeOH (0.3 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with and extracted three times with EtOAc. The combined organics were dried (MgSO4) and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 58 as the bis TFA salt, ES
(+) MS m1e = 460 (M+1).
[05061 EXAMPLE 32 O _~ cl ~NH NH
NaOH ~
56 MeOH HN S
--------=

HOC N~ J

[05071 Compound 59: 2M NaOH (I mL) was added to a solution containing 56 (0.6 g, 1.2 mmol) in MeOH (10 mL). The reaction mixture was stirred for 10 minutes. The mixture was then concentrated followed by the addition of water (3 mL). Aqueous IM HC1 was added until solid precipitated from the solution. The solid was collected and dried to yield 59 (0.4 g, 70%), ES (+) MS m/e = 474 (M+1).
(0508] EXAMPLE 33 O
N
Amine, HATU HN ~S~-NH NH
DIPEA, DMF =-"./~. 59 N-R-~
O
~ ~ ' R = CN- - -N N- - HN- -(0509] Compo'und 60A: HATU (0.136 g, 0.36 mmol) was added to a solution containing 59 (0.085 g, 0.18 mmol), Hunig's base (0.16 mL, 0.9 mmol), pyrrolidine (26 mgs, 0.36 rrzrnol) in DMF (3 mL). The reaction mixture was heated to 70 C
and stirred for I hour. The reaction was cooled to room temperature. The reaction mixture was diluted with H20. The aqueous layer was extracted twice with EtOAc.
The combined organic phases were dried with MgSOa, filtered, and concentrated.

The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 60A as the bis TFA salt, ES (+) MS m/e =
527 (M+1).
[0510] Compound 60B: HATU (0.136 g, 0.36 mmol) was added to a solution containing 59 (0.085 g, 0.18 mmol), Hunig's base (0.16 mL, 0.9 mmol), N-methyl piperazine (36 mgs, 0.36 mmol) in DMF (3 mL). The reaction mixture was heated to 70 C and stirred for 1 hour. The reaction was cooled to room temperature., The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc.
Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 60B as the tris TFA salt, ES (+) MS m/e = 556 (M+1).
[0511] Compound 60C: HATU (0.136 g, 0.36 mmol) was added to a solution containing 59 (0.085 g, 0.18 mmol), Hunig's base (0.16 mL, 0.9 mmol), methanesulfonamide (30 mgs, 0.36 mmol) in DMF (3 mL). The reaction mixture was heated to 70 C and stirred for overnight. The reaction was cooled to room temperature. The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 60C as the bis TFA salt, ES
(+) MS m/e = 551 (M+1).
[0512] EXAMPLE 34 O O-Cl ~N NH
LiBEt3H HO 11 ~ NH
57 THF, -78 C HN~\/ g~

N J __ N
N~ J

[0513] Compound 61: LiBEt3H (0.3 mL, 1.OM in THF) was added to a pre-cooled solution of 57 (73 mgs, 0.15 mmol) in THF (5 mL) at -78 C. The reaction mixture was stirred at -78 C for 1 hour and warmed to room temperature. The reaction mixture was diluted with 1M NaHCO3 and extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 61 as the bis TFA salt, ES (+) MS m/e = 460 (M+1).
[0514] EXAMPLE 35 0 (CI
MeMgBr HO --NH NH
~ ~
87 THF HN"'~S
IV ~N

N~ I J
N
[0515] Compound 62: Methyl magnesium bromide (0.2 mL, 3.OM in EtzO) was added to a solution of 57 (75 mgs, 0.15 mmol) in THF. The reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with H20 and extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 62 as the bis TFA salt, ES
(+) MS m/e = 488 (M+1).
[0516] EXAMPLE 36 DMF O NaH O ci methanesulfonamide ~ N NH
p S NH rI ~ N H
57 HN'-~,/~S
N

N~ I NJ

[0517] Compound 63: 60%wt of NaH (20 mgs, 0.5 mmol) was added to a solution containing 57 (50 mgs, 0.1 mmol) and methanesulfonamide (20mgs, 0.2 mmol) in DMF (3 mL). The reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with H20 and extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 63 as the bis TFA salt, ES (+) MS m/e = 552 (M+1).
[0518] EXAMPLE 37 o 0-ci N NH
NaOH ~ f>NH
57 MeOH HO2C'1 HN' V 'S

N N N' 64 INJ

[0519] Compound 64: 2M NaOH (2.6 mL) was added to a solution of 57 (1.28 g, 2.6 mmol) in MeOH (20 mL). The reaction mixture was stirred for 10 minutes. Concentrated to remove methanol and added H20 (3 mL). Added 1M
HCI until solid precipitated from the solution. Filtered, collected, and dried precipitate.as 64 (1.2 g, 99%), ES (+) MS m/e = 474 (M+1).
[0520] EXAMPLE 38 O-Cl O R ~ N ~NH
~'-NH
Amine, HATU % HN g DIPEA, DMF

NN
N
N

R = CN- - -N N- - O N- - HO--CN- -HO4,CN. - HO/,.,/~N--- ]N- - HO~N- -v HO

[0521] Compound 65A: HATU (0.1 g, 0.27 mmol) was added to a solution containing 64 (0.07 g, 0.13 mmol), Hunig's base (0.12 mL, 0.69 mmol), pyrrolidine (19 mgs, 0.27 mmol) in DMF (2 mL). The reaction mixture was heated to 70 C and stirred for- 1 hour. The reaction was cooled to room temperature. The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 65A as the bis TFA salt, ES (+) MS m/e = 527 (M+1).
105221 Compound 65B: HATU (0.1 g, 0.27 mmol) was added to a solution containing 64 (0.07 g, 0.13 mmol), Hunig's base (0.12 mL, 0.69 mmol), N-methyl piperazine (28 mgs, 0.27 mmol) in DMF (2 mL). The reaction mixture was heated to 70 C and stirred for 1 hour. The reaction was cooled to room temperature.
The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc.
Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 65B as the tris TFA salt, ES (+) MS m/e = 556 (M+1).

[0523] Compound 65C: HATU (0.1 g, 0.27 mmol) was added to a solution containing 64 (0.07 g, 0.13 mmol), Hunig's base (0.12 mL, 0.69 mmol), morpholine (24 mgs, 0.27 mmol) in DMF (2 mL). The reaction mixture was heated to 70 C and stirred for 1 hour. The reaction was cooled to room temperature. The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 65C as the bis TFA salt, ES (+) MS m/e = 543 (M+1).
[0524] Compound 65D: HATU (0.1 g, 0.27 mmol) was added to a solution containing 64 (0.07 g, 0.13 mmol), Hunig's base (0.12 mL, 0.69 mmol), 3-hydroxyazetidine hydrochloride (30 mgs, 0.27 mmol) in DMF (2 mL). The reaction mixture was heated to 70 C and stirred for 1 hour. The reaction was cooled to room temperature. The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was _ lyophilized under high-vacuum to yield 65D as the bis TFA salt, ES
(+) MS m/e = 529 (M+1).
[0525] Compound 65E: HATU (0.1 g, 0.27 mmol) was added to a solution containing 64 (0.07 g, 0.13 mmol), Hunig's base (0.12 mL, 0.69 mmol), R(+)-3-pyrrolidinol (24 mgs, 0.27 mmol) in DMF (2 mL). The reaction mixture was heated to 70 C and stirred for 1 hour. The reaction was cooled to room temperature.
The reaction mixture was diluted with Ha0. Extracted the aqueous layer with EtOAc.
Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 65E as the bis TFA salt, ES (+) MS m/e = 543 (M+1).
[0526] Compound 65F: HATU (0.1 g, 0.27 mmol) was added to a solution containing 64 (0.07 g, 0.13 mmol), Hunig's base (0.12 mL, 0.69 mmol), S(+)-3-pyrrolidinol (24 mgs, 0.27 mmol) in DMF (2 mL). The reaction mixture was heated to 70 C and stirred for 1 hour. The reaction was cooled to room temperature.
The reaction mixture was diluted with Ha0. Extracted the aqueous layer with EtOAc.

Combined the organics, dried with MgSO4a filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 65F as the bis TFA salt, ES (+) MS m/e = 543 (M+1).
[0527] Compound 65G: HATU (0.1 g, 0.27 mmol) was added to a solution containing 64 (0.07 g, 0.13 mmol), Hunig's base (0.12 mL, 0.69 mmol), 3-hydroxypiperidine (29 mgs, 0.27 mmol) in DMF (2 mL). The reaction mixture was heated to 70 C and stirred for 1 hour. The reaction was cooled to room temperature.
The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated.
The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 65G as the bis TFA salt, ES (+) MS m/e =
557 (M+1).
10528] Compound 65H: HATU (0.1 g, 0.27 mmol) was added to a solution containing 64 (0.07 g, 0.13 mmol), Hunig's base (0.12 mL, 0.69 mmol), R(+)-3-pyrrolidinol (24 mgs, 0.27 mmol) in DMF (2 mL). The reaction mixture was heated to 70 C and stirred for 1 hour. The reaction was cooled to room temperature.
The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc.
Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 65H as the bis TFA salt, ES (+) MS m/e = 543 (M+1).
[0529] EXAMPLE 39 o 0-ci H Ci DIPE A, DMF HN~.CS~ -NH NH

N ~N

N~ IN~ 66 [0530] Compound 66: 37 (0.67 g, 2.0 mmol) was added to a solution containing 28 (0.67 g, 2.0 mmol) and Hunig's base (1.4 mL, 8.0 mmol) in DMF
(15 mL). The reaction mixture was heated to 100 C for 1 hour. The reaction was cooled to room temperature. The reaction mixture was diluted with H20.
Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel using 10% MeOH in DCM to afford 66 (0.45 g, 54%), ES (+) MS m/e =
416 (M+1).
[0531] EXAMPLE 40 CN
0 _ CI
3s N H NH
H Cl DIP EA, DMF HN S~N

N N

[0532] Compound 67: 39 (0.69 g, 2.0 mmol) was added to a solution containing 28 (0.67 g, 2.0 mmol) and Hunig's base (1.4 mL, 8.0 mmol) in DMF
(15 mL). The reaction mixture was heated to 100 C for 1 hour. The reaction was cooled to room temperature. The reaction mixture was diluted with H20.
Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSOa, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel using 10% MeOH in DCM to afford 67 (0.40 g, 49%), ES (+) MS m/e =
440 (M+1).
10533] EXAMPLE 41 Cl ~

N-N ci DIP EA, DMF Q\/NH
~ 90 C ~( 1 1- ~ \N gYNH
N- N-N HN_/ ~N
9A \ \N 68 N=~

[0534] Compound 68: This compound was made according to procedures towards the synthesis of 10, except that 9A and 37 was used in place of 9 and respectively, ES (+) MS m/e = 429 (M+1).
[0535] EXAMPLE 42 CI p N,N ci 37 OyNH
I / \N gYNH
N-=~ DIPEA, DMF N-N HN N

9 ~ ~N- 69 N-=-~
[0536] Compound 69: This compound was made according to procedures towards the synthesis of 10, except that 37 was used in place of 3, ES (+) MS
m/e =
429 (M+1).
[0537] EXAMPLE 43 13 N Boc D1PEA' DMF HN~S-NH C~ HCa 90oC H a N ~ -~
28 ~ N
~ ~J NaH, DMF
N 9(}oC

~ ,~~-NHoc HN S 1) HCI, dioxanes N 2) 3-chloropheny) isocyanate ,~ Dlf'EA, THF
N

CI
O r ~ ~--NH NH
HNS
N .
Nl \ ,j 72 N
[0538] Compound 70: 13 (0.86 g, 3.5 mmol) was added to a solution containing 28 (0.55 g, 3.5 mmol) and Hunig's base (1.2 mL, 7.1 mmol) in DMF
(12 mL). The reaction mixture was heated to 90 C and stirred for 1 hour. The reaction mixture was cooled to room temperature. The reaction mixtwre was diluted with H20. Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel using 100% EtOAc to afford 70 (0.5 g, 39%), ES
(+) MS m/e = 362 (M+1).
10539] Compound 71: 60%wt of NaH (0.11 g, 0.66 mmol) was added to a solution containing 70 (0.2 g, 0.55 mmol) and 4-fluoropyridine hydrochloride (0.09 g, 0.66 mmol) in DMF (2 mL). The reaction mixture was heated to 90 C and stirred overnight. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel using 100% EtOAc to afford 71 (0.09 g, 36%), ES (+) MS m/e = 439 (M+l).

[0540] Compound 72: HCl (1 mL, 4.OM in dioxanes) was added to a solution of 71 (0.09 g, 0.2 mmol) in dioxanes (1 mL). The reaction mixture was stirred for I
hour and concentrated. The resulting residue was dissolved in Hunig's base (0.21 mL) and THF (5 mL). 3-chlorophenyl isocyanate (56 mgs, 0.36 mmol) was added and the reaction stirred for 3 hours. The reaction mixture was concentrated.
The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 72 as the bis TFA salt, ES (+) MS m/e =

(M+1).
[05411 EXAMPLE 44 1.) triphosgene ~ CN CH3CN, 75 C 0 O O CN
3 , 3 _~SIN H2N C! H CI

O

~ N HBr 73 S-~NH2 LiBH4 THF, MeOH
70 C HO 'N O CN
S N N CI
H H

O 07cl N
Ct j NH NH

N
NJ NaH, THF N N N
!~I 75 9 \ NJ

[0542] Compound 73: Triphosgene (0.74 g, 2.5 mmol) was added to a solution containing 4-amino-2-chlorobenzonitrile (1.05g, 6.9 mmol) in acetonitrile (28 mL). The reaction mixture was heated to 75 C and stirred for 1.5 hours.
The reaction was cooled to room temperature. A solution containing (2-amino-thiazol-5-yl)-acetic acid methyl ester hydrobromide (1.58 g, 6.2 mmol) [See Patent Application Publication US 2006/0035908], and Et3N (4.4 mL, 31.2 mmol) in acetonitrile (12 mL) was added to the reaction mixture and stirred for 15 minutes.
The reaction mixture was diluted with HZO. The aqueous layer was extracted with EtOAc. The combined organics were dried with MgSO4a filtered, and concentrated.
The crude residue was triturated with DCM and hexanes to afford 73 (1.9 g, 87%), ES (+) MS m/e = 351 (M+1).
[0543] Compound 74: LiBH4 (0.48 g, 21.6 mmol) was added to a solution containing 73 (1.9 g, 5.4 mmol) in THF (50 mL) and MeOH (5 mL). The reaction mixture was heated to 70 C for overnight. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with H20 and the aqueous layer was extracted with EtOAc. The combined organics vvere dried with MgSO4, filtered, and concentrated to afford 74 (1.7 g, 97%), ES (+) MS m/e = 323 (M+1).
[0544] Compound 75: 60%wt of NaH (52 mgs, 1.3 mmol) was added to a solution of 4-chlorothieno[3,2-d]pyrimidine (63 mgs, 0.4 mmol) and 74 (0.12 g, 0.4 mmol) in THF (4 mL). The reaction mixture was stirred for overnight. The reaction mixture was diluted with H20 and extracted aqueous layer with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 75 as the bis TFA salt, ES (+) MS m/e = 457 (M+1).
[0545] EXAMPLE 45 1)1,1'-th9ocarbony1diimidazole THF
2) 1,2-diamino-3,4-diffuorobenzene NHZ 3) DCC, 50 C ~ N
Y' Boe "~I ~~
N ~ ~
~ HN
H 4) HCt, dioxanes HzN

105461 Compound 76: 1,1'-thiocarbonyldiimidazole (0.68 g, 4.6 mmol) was added to a solution containing [2-(4-amino-phenyl)-ethyl]-carbamic acid t-butyl ester (1.1 g, 4.6 mmol). The reaction mixture was stirred for 30 minutes. 1,2-diamino-3,4-difluorobenzene (0.66 g, 4.6 mmol) was added to the reaction mixture and stirred for 3 hours. DCC (0.94 g, 4.6 mmol) was added and the reaction mixture was heated to 50 C for 2 hours. The reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was diluted with H20 and extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel using 40% EtOAc in hexanes to obtain solid. The resulting solid was dissolved in dioxanes (5mL) and HCI (3 mL, 4.OM in dioxanes) was added. The reaction mixture was stirred for overnight and concentrated to afford 76 (1.45 g, 87%), ES (+) MS m/e = 289 (M+1).
[0547] EXAMPLE 46 H
CI NN
IV 76 HN ~. , HN

N- DIPoEA, DMF N N F F

[0548] Compound 77: 76 (0.3 g, 0.84 mmol) was added to a solution containing 9 (0.14 g, 0.84 mmol) and Hunig's base (0.7 mL, 4.2 mmol) in DMF (5 mL). The reaction mixture was heated to 90 C and stirred for 1 hour. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with H20 and extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel using 5% CH3CN in EtOAc to afford 77 (0.11 g, 31 %), ES (+) MS m/e = 421 (M+1).
[0549] EXAMPLE 47 1) 1,1'-thiocarbonyldiimidazole THF
2) 1,2-diamino-3,4-difluorobenzene NHZ 3) DCC, 50 C N

Boc. \ ( \ I HN / ~ F
H 4) HCI, dioxane H2N

j05501 Compound 78: This compound was made according to procedures towards the synthesis of 76 except that 1,2-diamino-3,5-difluorobenzene was used in place of 1,2-diamino-3,4-difluorobenzene, ES (+) MS m/e = 289 (M+1).
[0551] EXAMPLE 48 1) 1,1'-thiocarbony1diimidazole THF
2) 1,2-diamino-4-chlorobenzene , N~N
NH2 3) :::e Boc. ~ I ~ I HN ~D CI

H ) I

[0552] Compound 79: This compound was made according to procedures towards the synthesis of 76 except that 1,2-diamino-4-chlorobenzene was used in place of 1,2-diamino-3,4-difluorobenzene, ES (+) MS m/e = 287 (M+1).
[0553] EXAMPLE 49 CI N..YN
CI HIN

N CI
N KI, DIPEA NN I
DMF 100 C N% 80 [0554] Compound 80: 79 (0.11 g, 0.3 mmol) was added to a solution containing 44 (0.066 g, 0.3 mmol), KI (51 mgs, 0.3 mmol) and Hunig's base (0.27 mL, 1.5 mmol) in DMF (5 mL). The reaction mixture was heated to 100 C for overnight. The reaction was cooled to room temperature. The reaction mixture was diluted with H20. Extracted the aqueous layer with EtOAc. Combined the organics, dried with MgSO4, filtered, and concentrated. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 80 as the bis TFA salt, ES (+) MS m/e = 431 (M+1).
[0555] EXAMPLE 50 cl o Q-CF3 \ CI ~ NH NH
N g NS/_ , N
N~ IN~
Kf, DiPEA N ~ I ~

[0556] Compound 81: This compound was made according to procedures towards the synthesis of 80, except that 3 was used in place of 79, ES (+) MS
m/e =
475 (M+1).
[0557] EXAMPLE 51 N.Boc Cl ~ ci ~N Boc IV N NH2 N~ ~ N N
N~ ~
~ J
N KI, DIPEA N

[0558] Compound 82: This compound was made according to procedures towards the synthesis of 80, except that 3-amino-piperidine-l-carboxylic acid t-butyl ester was used in place of 79, ES (+) MS m/e = 345 (M+1).
[0559] EXAMPLE 52 Boc I
CI I ~ NH
/ ~ Boc ~
CI HZNNH ~N

NN + N N N I N
N KI, DIPEA N

[0560] Compound 83: This compound was made according to procedures towards the synthesis of 80 except that (4-amino-phenyl)-carbamic acid t-butyl ester was used in place of 79, ES (+) MS m/e = 353 (M+l).

[05611 EXAMPLE 53 CN CN
p ci O 0cl ci r' ~ NH NH N NH
HN~~~S/' Ki, DIPEA NH
{~~g DMF, 100oC
N N

105621 Compound 84: This compound was made according to procedures towards the synthesis of 80, ES (+) MS m/e = 466 (M+1).

N CO2Me NaH, DMF N' COzMe ~
N \ I ~N N COzMe , NO2 NO2 N ~ ( 1) H2, Pd/C
MeOH
2) formamidine acetate DIPEA, nBuOH, 110 C

OH ~ OH
IVN~ N N
~
N~ N J
N

DMF, 90 C

ci ~ Cf N- f~
J
N N~ I J
N

[0564] Compound 85 and 85A: 2-iodopropane (4.0 mL, 40.0 mmol) was added to a solution of 5 (2.3 g, 13.5 mmol) and 60% wt of NaH (0.68 g, 16.9 mmol) in DMF (50 rnL). The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with H20. Separated the layers and the aqueous layer was extracted with EtOAc. The combined organics were dried with MgSOa, filtered, and concentrated. Purified the residue by column chromatography on silica gel using 30% EtOAc in hexanes to afford 85A (0.66 g, 23%), ES (+) MS m/e = 214 (M+1) and using 40% EtOAc in hexanes to afford 85 (1.09 g, 38%), ES (+) MS m/e = 214 (M+1).
[0565] Compound 86: This compound was made according to procedures towards the synthesis of 46, except that 85 was used in place of 45, ES (+) MS
m/e =
179 (M+1).
[0566] Compound 86A: This compound was made according to procedures towards the synthesis of 46, except that 85A was used in place of 45, ES (+) MS m/e = 179 (M+l).
105671 Compound 87: This compound was made according to procedures towards the synthesis of 47, except that 86 was used in place of 46, ES (+) MS
m/e =
197 (M+1).
[0568] Compound 87A: This compound was made according to procedures towards the synthesis of 47, except that 86A was used in place of 46, ES (+) MS m/e =197 (M+1).
[0569] EXAMPLE 55 ~ Ci 3 N ~-~NH
--NH
N N DIPEA, DMF HN 81 N~ ~ N~ 90 C NN -N
N
J

[0570] Compound 88: This compound was made according to procedures towards the synthesis of 10, except that 87A was used in place of 9, ES (+) MS
m/e = 491 (M+1).

[0571] EXAMPLE 56 / \
D ~ F
N
CI 4 ~NH NH
' --~ HN S
N N DIPEA, EA, DMF
N\ 90 C N ~N
N N~ I ~
N

[05721 Compound 89: This compound was made according to procedure towards the synthesis of 10, except that 87A and 4 were used in place of 9 and respectively, ES (+) MS m/e = 441 (M+1).
[05731 EXAMPLE 57 o 0-ci NH
CI 37 ~-NH
HN" S
~ Z DIPEA DMF
NX + N 90 C ~ N N N
J I
N N!~

(05741 Compound 90: This compound was made according to procedures towards the synthesis of 10, except that 87A and 37 were used in place of 9 and 3 respectively, ES (+) MS m/e = 457 (M+1).
[0575] EXAMPLE 58 H
' Di 79 NYN
aN-z-NI 90 DIPEA, DMF HN HN
NJ J N N CI
N~ ! I
87A N~' 91 [0576] Compound 91: This compound was made according to procedures towards the synthesis of 10, except that 87A and 79 were used in place of 9 and 3 respectively, ES (+) MS m/e = 447 (M+1).
[0577] EXAMPLE 59 0-ci C1 37 N o DIPEA DMF
90dC HNS~-NH NH
NN~ ~N

[0578] Compound 92: This compound was made according to procedures towards the synthesis of 10, except that 87 and 37 were used in place of 9 and respectively, except for using 46 in place of 1.8 and 5 in place of 1.3. ES
(+) MS m/e = 457 (M+1).
[05791 EXAMPLE 60 HO H0~
~ Co2Me NaH, DMF N CO2Me N CO2Me N ~ ! ~ IV~~ ~I
N02 HOBr NO2 NO2 1) H2, Pd/C
MeOH
2) formamidine acetate DIPEA, nBuOH, 110 C

HO OH HO~ OH
N, ' N N N
N ~ J
N \
N

1 DMF, 90 C

CI CI CI- CI
N N N
N J
N' N I N

[0580] Compound 93 and 93A: These compounds were made according to procedures towards the synthesis of 44 and 44A except that 3-bromo-l-propanol was used in place of 2-iodopropane, ES (+) MS m/e = 230.
[0581] Compound 94: This compound was made according to procedures towards the synthesis of 46, except that 93 was used in place of 45, ES (+) MS
m/e =
195 (M+1).
[0582] Compound 94A: This compound was made according to procedures towards the synthesis of 46, except that 93A was used in place of 45, ES (+) MS m/e = 195 (M+1).
[0583] Compound 95: This compound was made according to procedures towards the synthesis of 47, except that 94 was used in place of 46, ES (+) MS
m/e =
231 (M+1).
[0584] Compound 95A: This compound was made according to procedures towards the synthesis of 47, except that 94A was used in place of 46, ES (+) MS ni/e = 231 (M+1).
[0585] EXAMPLE 61 o ci 37 _ ~1 N NH NH
CI Ci C DIPEA, DMF Ci HN/ / 'g/~

' N' N_ N
N N

Cl O
N ~-NH
1.) MeS"Na+ 01 ~NH
DMF _-O HN S

2.) mCPBA, DCM \'N
~ 97 [0586] Compound 96: This compound was made according to procedures towards the synthesis of 51, except that 95 was used in place of 44, ES (+) MS
m/e =
491 (M+1).

[05871 Compound 97: This compound was made according to procedures towards the synthesis of 53 and 54B, except that 96 was used in place of 51, ES (+) MS m/e = 535 (M+1).

ct DIPEA, iDMFt N ~~ O~'NH
90 C HN" S/õNH

N

N

[0589] Compound 98: Pyrrolidine (16 mgs, 0.02 mmol) was added to a solution containing 96 (60 mgs, 0.01 mmol), Hunig's base (0.05 mL, 0.3 mmol), and KI (2 mgs) in DMF (3 mL). The reaction mixture was heated at 90 C overnight.
The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude residue was purified by prep RP-HPLC. The fractions containing pure compound were consolidated and concentrated. The residue thus obtained was lyophilized under high-vacuum to yield 98 as the tris TFA
salt, ES (+) MS m/e = 526 (M+1).
[0590] EXAMPLE 63 cl C4__ 37 O
~NH
CI poF~, DMF Ct ~\'NH
N N HN,'i,~,.S/
N1) N ~N

~ ~ C1 O\1 N ~"NH' pyrrolidine, KI CN _ 11 }--NH
DlPEA, DMF, 90 C ~ HN S

N

N ~ ~
N J

[0591] Compound 99: This compound was made according to procedures towards the synthesis of 51, except that 95A was used in place of 44, ES (+) MS m/e = 491 (M+1).
[0592] Compound 100: This compound was made according to procedures towards the synthesis of 98, except that 99 was used in place of 96, ES (+) MS
m/e =
526 (M+1).
[05931 EXAMPLE 64 O
~NH 0 H2, Pd/C
N ~ CI N~ JNH MeOH
)~/NH ~N
02N K2CO3, DMF 02N

O
N---\ ~NH

N--\-NH
~N ~
H2N~ KI1DIPEA N~ ~~

[0594] Compound 101: 2-chloro-N-phenylacetamide (0.15 g, 0.9 mmol) was added to a solution containing 4-nitroimidazole (0.1 g, 0.9 mmol) in DMF (5 mL).
The reaction mixture was heated to 65 C for 1 hour. The reaction mixture was diluted with H20. Separated the layers and the aqueous layer was extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to afford 101 (0.22 g, 100%), ES (+) MS m/e = 247 (M+1).
[0595] Compound 102: 10% wt. Pd/C (0.1 g, 0.09 mmol) was added to a solution containing 101 (0.22 g, 0.88 mmol) in 10 mL of methanol. The mixture was stirred under a hydrogen atmosphere at ambient temperature. After 3 hours, the reaction mixture was filtered thru a plug of Celite. The resulting filtrate was concentrated under reduced pressure to afford 102 (0.19 g, 100%).

[0596] Compound 103: This compound was made according to procedures towards the synthesis of 80 except that 102 was used in place of 79, ES (+) MS
m/e = 361 (M+l).
[0597] EXAMPLE 65 CI ~ ~ / NO2 H N HCIx HzN 104 ~ ( N HN
H
N DIPEAd DMF NIN N
28 90 C ~ N! 105 ~ NO2 BocN~~ HN ~ ~
~NBoc N N
MsO 106 ~ I
K2CO3, DMF, 80 C N 107 + N02 BocN HN \ I

IV N-a N

[0598] Compound 105: This compound was made according to example 10 except that 28 and 104 sere used in place of 9 and 3, respectively. ES (+) MS
m/e =
285 (M+1).
[0599] Compounds 107 and 108: A mixture of 105, 106, and K2C03 in DMF was heated at 80 'C. After 4.5 h, the mixture was concentrated and the residue was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic phases were dried (Na2SO4) and concentrated. The crude residue thus obtained was purified by column chromatography (Si02; 0 to 5% MeOH in EtOAc) to yield 50 mg of 107 and 108 mg of 108. 107: Rf0.59 (SiO; 5% MeOH in EtOAc), ES (+) MS m/e = 482 (M+1). 108:
Rf 0.47 (SiO; 5% MeOH in EtOAc), ES (+) MS m/e = 482 (M+1).

/ {
BocN~ HN ~ ( 1 atm H2, Pd/C BocN~ HN ~
N
N~ ( J N MeOH NN N
N
~ { J 109 H
1)1,1'-thiocarbonyldiimidazole / NI N
THF
2) 1,2-diamino-4-fluorobenzene NN/
~ {
3) DCC, 500C HN _ N - NI F
4) HCI, dioxanes N~ { NJ x 3 HCI

[0601) Compound 109: This compound was made according to procedures towards the synthesis of 15 except that 107 was used in place of 14. ES (+) MS
m/e = 452 (M+1).
[0602] Compound 110: This compound was made according to procedures towards the synthesis of 76 except that 109 was used in place of [2-(4-amino-phenyi)-ethyl]-carbamic acid t-butyl ester and 1,2-diamino-4-fluorobenzene was used in place of 1,2-diamino-3,4-difuorobenzene. ES (+) MS m/e = 586 (M+1).
[06031 EXAMPLE 67 " ~/N02 NH2 Bo ~ r~I' ( ~ a ~.y/HN ~ 1 atm H2, Pd/C Bo HN
-N
J MeOH N N 111 N 108 cN NJ

1) 1,1'-thiocarbonyldiimidazole H THF ~, N H
2) 1,2-diamino-4-fluorobenzene lj 3) DCC, 50 C HN HN ~ I N~~
4) HCI, dioxanes N'~ ~ N F
N~ N x 3 TFA

[0604] Compound 111: This compound was made according to procedures towards the synthesis of 15 except that 108 was used in place of 14. ES (+) MS
m/e = 452 (M+1).
[0605] Compound 112: This compound was made according to procedures towards the synthesis of 76 except that 111 was used in place of [2-(4-amino-phenyl)-ethyl]-carbamic acid t-butyl ester and 1,2-diamino-4-fluorobenzene was used in place of 1,2-diamino-3,4-difuorobenzene. The crude product was purified using RP-preparative HPLC. ES (+) MS m/e = 586 (M+1).
[06061 EXAMPLE 68 N ~ CI
i O HN N 0 114 N=-/
NH
ca CF3 DIPEA, DMF N' HN 2TFA CF3 NH2 100 C HN \N 115 HCI x 113 N_ [0607] Compound 115: To a solution of 114 (0.22 g, 0.6 mmol) and DIPEA
(0.34 mL, 1.9 mmol) in DMF (3.0 mL) was added 114 (0.10 g, 0.60 mmol, Chern, J.-H. et al. Bioorg. Med. Chem. Lett., 2004, 2519). The resulting solution was stirred at 100 C for 1 hour and was then cooled to room temperature. The solvents were removed under reduced pressure using high-vacuum and a heated water bath. The resulting residue was diluted with methanol and purified by prep HPLC to afford 115 (40 mg, 10%) as a white solid. ES (+) MS m/e = 427 (M+1).
[0608] EXAMPLE 69 F3C ', F3C \ ~ ~ /
~
O

NH

C5 YNH DIPEA, n-BuOH HN-- N
H2N--' N 910 C HN" /\ 2TFA

106091 Compound 116: A mixture of 3 (100 mg, 0.303 mmol), 114 (47 mg, 0.303 mmol), and DIPEA (1.0 mL) in n-butanol (1.0 mL) was stirred at 110 C for hours. The solution was then concentrated and the residue was purified by prep. RP-HPLC. The fractions containing pure compound were combined and concentrated.
The residue thus obtained was lyophilized under high-vacuum to yield 40 mg of a solid. ES (+) MS m/e = 449 (M+1).

/N

N ~-NH
Et02C~ CI 1 DIPEA39 ,DMF HC HN" S~NH
~
N I N 90 C N ' \ JN
N~ NJ 2) LiBEtgH
THF, -78 C N ~ N

106111 Compound 117: Add 39 (1.0 mmol) to a solution containing 47A (1.0 mmol) and Hunig's base (3.0 mmol) in DMF.(10 mL). Heat the reaction mixture to 90 C for 1 hour and cool to room temperature. Dilute the reaction mixture wit, H20. Extract the aqueous layer with EtOAc. Combine organics, dry with MgSO4, filter and concentrate. Purify by column chromatography on silica gel using 10%
MeOH in hexanes. Dilute the resulting residue with THF (lOmL) and cool to -78 C. Add Li13Et3H (2.0 mL, 1.OM in THF) to the reaction mixture. Stir the reaction mixture at -78 C for 1 hour and warm to room temperature. Dilute the reaction mixture with IM NaHCO3 and extract with EtOAc. Combine organics, dry with MgSO4, filter, and concentrate. Purify resulting residue by prep RP-HPLC
to afford 117.
[0612] EXAMPLE 71 N
CF

~ 3 N Et0 C ci 1) 39A HO ~NH NH
2 ~ DIPEA,DMF HN"
N ~ N 90 C
N - N N
NJ 2) Li8Et3H N~
THF, -78 C N

[0613) Compound 118: Add 39A (1.0 mmol) to a solution containing 47A (1.0 mmol) and Hunig's base (3.0 mmol) in DMF.(10 mL). Heat the reaction mixture to 90 C for 1 hour and cool to room temperature. Dilute the reaction mixture with H20. Extract the aqueous layer with EtOAc. Combine organics, dry with MgSO4, filter and concentrate. Purify by column chromatography on silica gel using 10%
MeOH in hexanes. Dilute the resulting residue with THF (lOmL) and cool to -78 C. Add LiBEt3H (2.0 mL, 1.OM in THF) to the reaction mixture. Stir the reaction mixture at -78 C for 1 hour and warm to room temperature. Dilute the reaction mixture with 1M NaHCO3 and extract with EtOAc. Combine organics, dry with MgSO4, filter, and concentrate. Purify resulting residue by prep RP-HPLC
to afford 118.

HO
NaH, DMF N CO2Me g N N COZMe HO~~Br NOz N~ ~ NO

1.) H2, Pd/C
MeOH
2.) formamidine acetate D1PE4, nBuOH, 110 C

OH HO
N~ N OH
N
~ N N, el:y"

SOCIZ
DMF, 90 C
CI Ci CI
N~ N N
N N~
CI~ N

[0615] Compound 119 and 119A: Add 4-bromo-l-butanol (35.0 mmol) to a solution containing 1.4 (23.4 mmol) and 60%wt of NaH (35.0 mmol) in DMF (50 mL). Stir the reaction mixture for 2 hours. Dilute the reaction mixture with H20.
Extract the aqueous layer with EtOAc. Combine organics, dry with MgSO4, filter and concentrate. Purify the residue with column chromatography on silica gel to isolate both 63 and 64.
[0616] Compound 120: Combine 119 (12 mmol) and 10%wt of Pd/C (0.6 mmol) in MeOH (30mL) with 1 atm H2, via balloon. Stir the reaction mixture overnight. Filter the reaction mixture thru a plug of Celite and concentrate to afford residue. Dilute residue with n-butanol (25 mL) followed by Hunig's base (25 mL).
Add formamidine acetate (13 mmol) and heat the reaction mixture to 110 C for 1 hour. Cool the reaction mixture to room temperature and concentrate. Dilute the reaction mixture with H20 and extract the aqueous layer with EtOAc. Combine organics, dry with MgSO4, filter, and concentrate to afford 120.
[0617] Compound 120A: Combine 119A (6 mmol) and 10%wt of Pd/C
(0.3 mmol) in MeOH (15mL) with I atm H2, via balloon. Stir the reaction mixture overnight. Filter the reaction mixture thru a plug of Celite and concentrate to afford residue. Dilute residue with n-butanol (13 mL) followed by Hunig's base (13 mL).
Add formamidine acetate (8 mmol) and heat the reaction mixture to 110 C for 1 hour. Cool the reaction mixture to room temperature and concentrate. Dilute the reaction mixture with H20 and extract the aqueous layer with EtOAc. Combine organics, dry with MgSOa, filter, and concentrate to afford 120A.
[0618] Compound 121: Add DMF (2.5 mL) to a solution containing 120 (7.6 mmol) in SOC12 (25 mL). Heat the heterogeneous reaction mixture to 90 C for 30 minutes. Cool the homogeneous solution for room temperature. Concentrate the reaction mixture. Dilute with EtOAc, followed by ice. Separate the layers and extract the aqueous layer with EtOAc. Combine organics and wash with saturated NaHCO3, followed by brine. Dry with MgSO4, filter, and concentrate to afford 121.
[0619] Compound 121A: Add DMF (1.3 mL) to a solution containing 120A (3.8 mmol) in SOC12 (13 mL). Heat the heterogeneous reaction mixture to 90 C for 30 minutes. Cool the homogeneous solution for room temperature.
Concentrate the reaction mixture. Dilute with EtOAc, followed by ice. Separate the layers and extract the aqueous layer with EtOAc. Combine organics and wash with saturated NaHCO3, followed by brine. Dry with MgSO4, filter, and concentrate to afford 121A:
[0620] EXAMPLE 73 ci 1) 37 DIPEA,DMF

N 2) pyrrolidine GI KI, DIPEA
121 DMF, 90 C

O 0-cl INJ I ~-NH NH N
~ S
N N-- ~ N
~ - ~

[0621] Compound 122: Add 37 (1.0 mmol) to a solution containing 121 (1.0 mmol) and Hunig's base (3.0 mmol) in DMF.(10 mL). Heat the reaction mixture to 90 C for 1 hour and cool to room temperature. Dilute the reaction mixture with H20. Extract the aqueous layer with EtOAc. Combine organics, dry with MgSO4, filter and concentrate. Purify by column chromatography on silica gel using 10%
MeOH in hexanes. Dilute the resulting residue in DMF (10 mL). Add KI (1.0 mmol), Hunig's base (1.0 mmol), and pyrrolidine (2.0 mmol). Heat the reaction mixture to 90 C. Cool the reaction mixture to room temperature. Dilute the reaction mixture with H20. Extract the aqueous layer with EtOAc. Combine organics, dry with MgSO4, filter and concentrate. Purify resulting residue by prep RP-HPLC
to afford 122.

Ci 1) 37 Ci D1PEA,DMF

2) pyrrolidine KI, DIPEA
UqA DMF, 90 C

N Cf 0 ~ ~ N ~--NH
HN$%, N ~= N
N\ I
N~ 123 [0623] Compound 123: Add 37 (1.0 mmol) to a solution containing 121A (1.0 mmol) and Hunig's base (3.0 mmol) in DMF.(10 mL). Heat the reaction mixture to 90 C for 1 hour and cool to room temperature. Dilute the reaction mixture with H20. Extract the aqueous layer with EtOAc. Combine organics, dry with MgSO4, filter and concentrate. Purify by column chromatography on silica gel using 10%
MeOH in hexanes. Dilute the resulting residue in DMF (10 mL). Add KI (1.0 mmol), Hunig's base (1.0 mmol), and pyrrolidine (2.0 mmol). Heat the reaction mixture to 90 C. Cool the reaction mixture to room temperature. Dilute the reaction mixture with H20. Extract the aqueous layer with EtOAc. Combine organics, dry with MgSO4, filter and concentrate. Purify resulting residue by prep RP-HPLC
to afford 123.
[0624] EXAMPLE 75 [0625] Formulation of Compounds 106261 The solubility of poorly soluble compounds are improved by making them as acid salts. Illustrative examples of such acids include methane sulfonic acid and citric acid. Solubility of these compounds can be additionally improved by the addition of solubility enhancing agents such as Tween-80 and PEG-400.
Illustrative formuations of poorly soluble compounds of the present invention include 10%I30%/60% , 5%/30%/65%, and 2.5%/30%/67.5% respectively of Tween-80, PEG-400 and water. The pH of these formulations can also also be varied to identify a range for optimal solubility.
[0627] EXAMPLE 76 [06281 Biochemical assays (See Figure 2).
[06291 Aurora A kinase assay 10630J Aurora A protein kinase assays contained 10mM Tris HCI, pH7.2, 10mM
MgC12, 0.1% BSA, 0.01%Triton X-100, 1mM DTT, 20p.M ATP, l20nM H3 peptide substrate, compound inhibitor (5% final DMSO concentration) and 25nM Aurora A
protein in a total volume of 40 1. Reactions were incubated at room temperature for 60 min, stopped with 28}t1 of 50mM EDTA pH9, and further incubated at room temperature for 60 min. An equal volume of stopped reaction was incubated with detection buffer containing 50mM HEPES pH 7.0, 0.5M KF, 0.1% BSA, 0.25 g/mL a-Phospho H3 antibody, and 0.016p.M StreptAvidin-XL665 for 60 min, and subsequently read on the Analyst (LjL BioSystems) at excitation 330-370nm, and detection 665nm, 620nm.
[0631] Aurora B kinase assay [0632] Aurora B protein kinase assays contained IOmM Tris HC1, pH7.2, 10mM
MgC12, 0.1% BSA, 0.01%Triton X-100, 1mM DTT, 80 M ATP, l20nM H3 peptide substrate, compound inhibitor (5% final DMSO concenttation) and 1.5nM Aurora B
protein in a total volume of 40 1. Reactions were incubated at room temperature for 60 min, stopped with 28 1 of 50mM EDTA pH9, and further incubated at room temperature for 60 min. An equal volume of stopped reaction was incubated with detection buffer containing 50mM HEPES pH 7.0, 0.5M KF, 0.1% BSA, 0.25 gg/mL oc-Phospho H3 antibody, and 0.016 M StreptAvidin-XL665 for 60 min, and subsequently read on the Analyst (LjL BioSystems) at excitation 330-370n.m, and detection 665nin, 620nm.
106331 HCS Cell Cycle Assay 106341 The HCS Cell Cycle assay is used to measure the amount of cells with DNA content of 4N or greater. Inhibiting Aurora kinases in cells can cause failed mitosis and endoreduplication. This yields cells with 4N DNA content or greater.
[0635] Protocol: Plate 10,000 cells per well in a 96 well, clear bottom plate.
(This assay is routinely done with HCT-I 16 cells, but has also been performed with a number of other adherent human cell lines.) Grow overnight. The next day, add compound to each well at the desired concentration. Incubate at 37 C for 16 hours.
Remove compound and fix cells with 4% Formaldehyde for 12 minutes at room temperature. Remove Formaldehyde and wash once with PBS. Add DNA stain in blocking solution (10% FBS in PBS) to the cells, and incubate for one hour at 37 C.
Remove stain solution and wash cells one time with PBS. Visualize the cells on a high content imager to quantitate the DNA content of the cells.
[0636] Lhosaho-Histone H3 HCS Assay [0637] The Phospho-Histone H3 HCS assay is done to measure a compounds ability to inhibit Aurora B in tumor cell lines. As Aurora B is inhibited, it is unable to phosphorylate Histone H3 on Serine 10, and this lack of phosphorylation can be measured by a high content imager.
[0635] Protocol: Plate 10,000 cells per well in a 96 well, clear bottom plate.
(This assay is routinely done with HCT-116 cells, but has also been performed with a number of other adherent human cell lines.) Grow overnight. The next day, add compound to each well at the desired concentration. Incubate at 37 C for one hour.
Remove compound and fix cells with 4% Formaldehyde for 12 minutes at room temperature. Remove Formaldehyde and permeabilize cells with 0.1% Triton X-100 for 5 minutes at room temperature. Remove Triton X-100 and wash once with PBS.
Block cells overnight with blocking solution (10% FBS in PBS) at 4 C. Remove blocking agent and add phospho-histone H3 Serine 10 antibody in blocking solution to the cells, and incubate for two hours at 37 C. Remove primary antibody solution and wash cells twice with PBS. Add a fluorescent antibody and DNA stain in blocking solution to the cells, and incubate for one hour at room temperature.
Remove secondary antibody solution and wash cells three times with PBS.
Visualize the cells on a high content imager to quantitate the levels of phospho-histone H3 Serine 10 in the cells.
[0639] EXAMPLE 77 [0640] Target Modulation studies (See Figure 1).
[0641] Nu/nu mice are subcutaneously injected into their hind flank with human HCT-l16 cells and 50% Matrigel (Becton-Dickinson). Human HCT-116 tumors are then allowed to grow to 400 mm3. The tumor bearing mice are then either given an administration of SPD or vehicle (Sigma-Aldrich) (orally, intravenously or intraperitoneally). At prescribed time points post dose, mice are anesthetized and blood taken via terminal cardiac puncture, and sacrificed. The HCT-116 tumors are excised from the mice, pulverized using liquid nitrogen-cooled mortar and pestle, and flash-frozen in liquid nitrogen. Tumor lysates are made from the pulverized samples by addition of lysis buffer.
[0642] For detection of response markers by Western blotting, the protein concentration of the lysates is determined by colorimetric detection. Twenty-five micrograms of protein is loaded per lane on an SDS-PAGE gel. Proteins.. are separated by gel electrophoresis, blotted onto nitrocellulose membranes, and probed using anti-Histone H3 and anti-phosphorylated Histone H3 antibodies, (both from Cell Signaling Technology) [0643] EXAMPLE 78 [0644] Maximum Tolerated Dose studies.
[06451 Maximum Tolerated Dose (MTD) is defined as the dose at which the mouse is no longer able to function normally and is determined by either significant toxicity (eg. body weight loss) or mortality. Mice (nu/nu) are sorted according to weight and randomized into groups prior to being dosed with a test compound, by oral, intravenous or intraperitoneal routes. Escalating doses of a test cmpound are used. Animal weights are measured daily for 5 days and about every 3 days after that until the animal is removed from the study due to body weight loss of >
20% or any alterations in physiological function that would affect normal function.
Clinical observations are performed throughout the study to note any toxicity and mice are monitored until the end of the study.

[0646] EXAMPLE 79 106471 Efficacy studies.
[064$] Nu/nu mice are subcuntaneously injected into their hind flank with human HCT-116 cells and 50% Matrigel (Becton-Dickinson). Human HCT-116 tumors are allowed to grow to 150-200 mm3. The tumor bearing mice are then either given an administration of a test compound or a vehicle control. The tumor dimensions (length [1 mm] and width [w mm]) are measured by electronic calipers and the tumor volume (mm) determined from the equation ([w2 X 1] -2). Weights of the mice and their respective tumor volumes are measured twice weekly until the animal is removed from the study, either because there is a body weight loss of greater than 20% or a tumor volume greater than 2000 mm3. Clinical observations are performed throughout the study, which usually lasted for up to 70 days after the initial implantation of the tumor cells. Tumor volume increases are compared to negative (vehicle) and positive controls. Percentage tumor growth inhibition (TGI) is calculated from the equation [(tumor volume T - tumor volume) :-tumor volume C) x 100, where T= treatment group and C= control or vehicle group. The tumor volume for both groups is usually determined at defined times after the administration of the last dose of compound. Survival plots (Kaplan-Maier) are also performed to examine the pattern of survival.
[0649] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

- APPENDIX -FDA Approved Oncology Drugs ,ist of Approved Oncology Drugs with Approved Indications Page 1 of 21 Drug Drug Trade Name Approved Use Manufacturer/Dist For the palliative treatment of inen with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the abarelix Plenaxis depot following: (1) risk of neurological Praecis compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia aldesleukin Prokine Treatment of adults with metastatic Chiron melanoma Aldesleukin Proleukin Treatment of adults with metastatic renal Chiron Cora cell carcinoma -- -Accel. Approv. (clinical benefit not established) Campath is indicated for the Alemtuzumab Campath treatment of B-cell chronic lymphocytic MillerLnsum ansl ILE
leukemia (B-CLL) in patients who have Partners LP
been treated with alkylating agents and who have failed fludarabine therapy.
Topical treatment of cutaneous lesions in alitretinoin Panretin patients with AIDS-related Kaposi's Ligand Pharmaceuti.
sarcoma.
Patients with leukemia, lymphoma and solid tumor malignancies who are receiving allopurinol Z l~oprim cancer therapy which causes elevations of G1axoSmithKline serum and urinary uric acid levels and who cannot tolerate oral therapy.
Single agent palliative treatment of patients altretamine Hexalen with persistent or recurrent ovarian cancer US Bioscience following first-line therapy with a cisplatin and/or alkylating agent based combination.
To reduce the cumulative renal toxicity amifostine Ethyol associated with repeated administration of US Bioscience cisplatin in patients with advanced ovarian cancer Accel. Approv. (clinical benefit not amifostine Eol established) Reduction of platinum toxicity US Bioscience in non-small cell lung cancer To reduce post-radiation xerostomia for amifostine Ethvol head and neck cancer where the radiation US Bioscience port includes a substantial portion of the parotid glands.
Accel. Approv. (clinical benefit not anastrozole Arimidex established) for the adjuvant treatment of AstraZeneca postmenopausal women with hormone receptor positive early breast cancer Conversion to regular approval for the adjuvant treatment of postmenopausal http://www.accessdata.fda.gov/scripts/cder/onctools/druglist.cfm 7/21/06 List of Approved Oncology Drugs with Approved' Indications Fage 2 of 2;
anastrozole Arimidex women with hormone receptor positive early AstraZeneca breastcancer Treatment of advanced breast cancer in AstraZeneca anastrozole Arimidex postmenopausal women with disease phaTmaceuticals progression following tamoxifen therapy.
For first-line treatment ofpostmenopausal anastrozole Arimidex women with hormone receptor positive or AstraZeneca hornzone receptor unknown locally advanced Pharmaceuticals or metastatic breast cancer.
Second line treatment of relapsed or arsenic trioxide Trisenox refractory APL following ATRA plus an Ceil T era eutic anthracyoline.
Therapy of patients with acute lymphocytie asparaginase Els~ar leukemia Merck ELSPAR is indicated in the therapy of patients with acute lymphocytic leukemia.
Asparaginase Elspar This agent is useful primarily in combination Merck 8e Co, Inc with other chemotherapeutic agents in the induction of remissions of the disease in pediatric patients.
For use for the treatment of patients with the following myelodysplasfic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if zaciti ipe Vidaza accompanied by neutropenia or Pharmion thrombocytopenia and requiring transfasions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia BCG Live TICE BCG Organon Teknika C
irst-line treatment of patients with bevacuzimab Avastin metastatic carcinoma of the colon and Genentech rectum (in combination with intravenous 5-fluorouracil-based chemotherapy) For the treatment by oral capsule of bexarotene capsules Tar retin cutaneous manifestations of cutaneous T-ce11 Ligand Pharmaceut lymphorna in patients who are refractory to at least one prior systemic thera y.
For the topical treatment of cutaneous bexarotene ael Tar retin manifestations of cutaneous T-cell Ligand pharmaceut lymphoma in patients who are refractory to at least one prior s stemie therapy.
bleomycin Blenoxane Bxistol- ers S uil Sclerosing agent for the treatment of bleomycin Blenoxane malignant pleural effusion (MPE) and Brist al-MXers Sauii prevention of reeurrent pleural effusions.

Accel. Approv. (clinical benefit not established) for the treatment of multiple http://%ww.accessdata.fda.gov/scripts/cder/onetools/druglist.cfm 7/2I/0i List of Approved Oncology Drugs with Approved Indications Page 3 of 2 myelorna patients who have received at least bortezomib Velcade two prior therapies and have demonstrated Millenium disease progression on the last therapy Conversion to regular approval for treatment bortezomib Velcade of multiple mycloma patients who have Millenium received as least one prior therapy Use in combination with cyclophoshamide as conditioning regimen prior to allogeneic busulfan intravenous Busulfex hematopoietic progenitor cell transplantation ~han Medical~In for chronic myelogenous leukemia.
busulfan oral Myleran Chronic Myelogenous Leukemia- palliative GlaxoSmithKline therapy calusterone Methosarb Phlacia Uo~ol CompanX
Accel. Approv. (clinical benefit subsequently established) Treatment of metaslatic breast cancer resistant to both paclitaxel and an anthracycline containing chemotherapy regimen or resistant to capecitabine Xeloda paclitaxel and for whom further Roche anthracycline therapy may be contraindicated, e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents Initial therapy of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
- -- - -Combination chemotherapy has shown a capecitabine Xeloda survival benefit compared to 5-FU/LV Roche alone. A survival benefit over 5FU/LV has not been demonstrated with Xeloda monotherapy.
Conversion to regular approval for treatment capecitabine Xeloda in combination with docetaacel of patients Roche with metastatic breast cancer after failure of prior anthracycline containing chemotherapy Adjuvant treatment in patients with Dukes' C colon cancer who have undergone capecitabine Xeloda complete resection of the primary tumor Roche when treatment with fluoropyrimidine therapy alone is preferred Palliative treatment of patients with ovarian carbonlatin Paraplatin carcinoma recurrent after prior Bxistol-Mvers S uil chemotherapy, including patients who have been previously treated with cisplatin.
Initial chemotherapy of advanced ovarian carboplatin Paraplatin carcinoma in combination with other Bristol-M ers Squil approved chemotherapeutic agents.
carmustine BCNU. BiCNU Bristol-M yers S uil carmustine Gliadel Treatment of patients with malignant glioma MGI Pharrna undergoing primary surgical resection http://www.accessdata.fda.gov/scripts/cder/onetools/druglist.efm 7/21/0( List of Approved Oncology Drugs with Approved Indications Page 4 of 2:
3I ' al,, "#õ " alõ!f S l,.ll lL:u 1I ::I1, J., ?': iI} ii For use in addition to surgery to prolong carmustine with survival in patients with recurrent Guilford Pharmacet I'olife rosan 201m lant Gliadel Wafer p p glioblastoma multifoxme who qualify for Inc, surgery.
Accel. Approv. (clinical benefit not celecoxib Celebrex established) Reduction of polyp number in eWe patients with the rare genetic disorder of familial adenomatous polyposis.
Accel. Approv. (clinical benefit not established) for treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-cetuximab Erbitax based chemotherapy (in combination with Imclone irinotecan); as a single agent, treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy For use in combination with radiation therapy (RT) for the treatment of locally or regionally advanced squamous cell ' carcinoma of the head and neck (SCCHN) or tuximab Brbitux Imelone as a singie agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.
chlorambucil Leukeran GlaxoSmithKline Metastatic testicular-in established combination therapy with other approved chemotherapeutic agents in patients with cisplatin Platinol nmetastatic testicular tumors whoc have g~stol-Mvers S ui1 already received appropriate surgical and/or radiotherapeutic procedures. An established combination therapy consists of Platinol, Blenoxane and Velbam.
Metastatic ovarian tumors - in established combination therapy with other approved chemotherapeutic agents: Ovarian-in established combination therapy with other approved chemotherapeutic agents in patients with metastatic ovarian tumors who is ati Platinol have already received appropriate surgical Bristol-Myers Squil and/or radiotherapeutic procedures. An established combination consists of Platinol and Adriamycin. Platinol, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received Platincl therapy.
as a single agent for patients with cisplatin Platinol transitional cell bladder cancer which is no Bristol-M e s S uil longer amenable to local treatments such as surgery and/or radiotherapy.
http://www.accessdata.fda.gov/scripts/cder/onctools/druglist.cfm 7/21/06 List of Approved Oncology Drugs with Approved Indications Page 5 of 2' I;,;n Il;:~ "I ." I1Y 'S 0:11 R";'11 11.1[
R.W. Johnson cladribine Leustatin 2-CdA Treatment of active hairy cell leukemia. Pharmace tical Res Institute Accel. Approv. (clinical benefit not established) for the treatment of pediatric clofarabine Clolar patients 1 to 21 years old with relapsed or Genzvme refractory acute lymphoblastic leukemia after at least two prior regimens cyclophosphamide Cytoxan, Neosar Bristol-M~ers Sauil cvclophosphamide Cytoxan Injection Bristol-Myers Squil cyclophosphamide Cytoxan Injection Bristol-Myers Squil cyclophosphamide Cytoxan Tablet Bristol-M ey rs Squil Pharmacia BcUp,jur cytarabine Cytosar-U CompanX
Accel. Approv. (clinical benefit not c arabine liposomal DepbCvt established) Intrathecal therapy of Skye Pharmaceutc;
I lymphomatous meningitis dacarbazine DTIC-Dome Bayer dactinomycin, Cosmegen Merck actinom, c dactinom,Xcin, Cosmegan Merck actinomycin D
Darbepoetin alfa Aranesp Treatment of anemia associated with chronic Amge , Inc renal failure.
Aranesp is indicated for the treatment of anemia in patients with non- myeloid Darbepoetin alfa Aranesp malignancies where anemia is due to the Amgen, Inc effect of concomitantly administered chemotherapy.
daunorubicin liposomal DanuoXome First line cytotoxic therapy for advanced, Nexstar, Inc.
HIV related Kaposi's sarcoma.
Leukemia/rnyelogenous/monocytic/erythroid daunorubicin. Daunorubicin of adults/remission induction in acute Bedford Labs daunomycin lymphocytic leukemia of children and adults.
daunorubicin, In combination with approved anticancer daunomycin Cerubidine drugs for induction of remission in adult Wyet Averst ALL.
for the treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, decitabine Daco en de novo and secondary MDS of all French- MGI PHARMA IN
American-British subtypes (refractory - -anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts http_llwww.accessdata.fda.gov/scripts/cder/onctools/druglist.cfin 7/21/0i List of Approved Oncology Drugs with Approved IndicatiDns Page 6 of 21 in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
Accel. Approv. (clinical benefit not established) treatment of patients with Denileukin diftitox Ontak persistent or recurrent cutaneous T-cell Seragen, Inc lymphoma whose malignant cells express the CD25 component of the IL-2 receptor Accel. Approv. (clinical benefit dexrazoxane Zinecard subsequently established) Prevention of Pharrnacia &
Upjoh cardiomyopathy associated with doxorubicin COmpan administration Conversion to regular approval for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic dexrazoxane Zinecard breast cancer who have received a Pharmacia & Upjoh cumulative doxorubicin dose of 300 mg/m2 Comuany and who will continue to receive doxorubicin therapy to maintain tumor control. It is not recommended for use with the initiation of doxorubicin therapy.
Accel. Approv. (clinical benefit subsequently established) Treatment of patients with locally advanced or metastatic docetaxel Taxotere Aventis Pharmaceut breast cancer who have progressed during anthracycline-based therapy or have relapsed during anthracycline-based adjuvant therapy.
Conversion to regular approval - treatment of locally advanced or metastatic breast docetaxel Taxotere cancer which has progressed during Aventis Pharmaceut anthracycline-based treatment or relapsed during anthracycline-based adjuvant therapy.
For locally advanced or metastatic non-small docetaxel Taxotere cell lung cancer after failure of prior Aventis Pharmaceul platinum-based chemotherapy.
for use in combination with cisplatin for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously docetaxel Taxotere received chemotherapy for this condition Aventis Pharmaceul cisplatin for the treatment of patients with u.nresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.
For use in combination with prednisone as a docetaxel Taxotere treatment for patients with androgen Aventis Pharmaceul independent (hormone refractory) metastatic prostate cancer http://www_accessdata.fda.gov/scripts/cder/onctools/druglist.cfm 7/21/0E

List of Approved Oncology Drugs with Approved Indications Page 7 of 2) ~;r~I~::~;'ll'.. ~f.Jd!!~1:N8:~u ~!!.~t.~(..'.!;a~~'d[=

For use in combination with doxorubicin docetaxel Taxotere and cyclophosphamide for the adjuvant Aventis Pharm ceu' treatment of patients with operable nodepositive breast cancer For use in combination with cyclophosphamide as a component of doxorubicin Adriam,ycin PFS adjuvant therapy in patients with evidence of Pharrnacia axillary node tumor involvement following resection of primary breast cancer doxorubicin Adriamycin,_Rubex Pharmacia & Upjoh CompanX
Ad_r_iam,v in PF Upjoh doxorubicin Injectionintravenous Antibiotic, antitumor agent. --ar~naciac4 Company in'ection Conversion to regular approval for treatment doxorubicin liposomal Doxil of patients with ovarian cancer whose Alza disease has progressed or recurred after platinum-based chemotherapy Accel. Approv. (clinical benefit not established) Treatment of AIDS-related doxorubicin liposomal Doxii Kaposi's sarcoma in patients with disease Sequus Pharmaceuti that has progressed on prior combination Inc.
chemotherapy or in patients who are intolerant to such therapy.
Accel. Approv. (clinical benefit not established) Treatment of metastatic Sequus Pharmaceuti doxoLubicin li on somal Doxil carcinorna of the ovary in patient with Inc.
disease that is refractory to both paclitaxel and platinum based regimens DROMOSTANOLONE DROMOSTANOLONE Eli Lilly PROPIONATE
DROMOSTANOLONE MASTERONE SYNTEX
PROPIONATE INJECTION
Diluent for the intrathecal administration of Elliott's B Solution Elliott's B Solution methotrexate sodium and cytarabine for the Orphan Medical Ini prevention or treatment of meningeal leukemia or lymphocytic lymphoma.
A component of adjuvant therapy in patients epirubicin Ellence with evidence of axillary node tumor Pharmacia & Upjoh involvement following resection of primary Cornpany breast cancer.
EPOGENB is indicated for the reatment of anemia related to therapy with zidovudine in HIV- infected patients. EPOGENB is indicated to elevate or maintain the red lood cell level (as manifested by the Epoetin alfa e 2en hematocrit or hemoglobin determinations) ArnQen Inc and to decrease the need for transfusions in these patients. EPOGEND is not indicated for the treatment of anemia in HIV-infected patients due to other factors such as iron or folate deficiencies, hemolysis or http://www.accessdata.fda.gov/scripts/cder/onctools/druglist.cfin 7/2I/06 List of Approved Oncology Drugs with Approvcd Indications Page 8 of 21 P' II;;;;; Ti" U9w:;i ILII Ili:a " u;;!' 2I Il.
gastrointestinal bleeding, which should be managed appropriately.
EPOGENB is indicated for the treatment of anemic patients (hemoglobin > 10 to _< 13 Egoetin alfa e o en g/dL) scheduled to undergo elective, Amgen, Inc noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions.
EPOGENB is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. EPOGEND is indicated to decrease the need for transfusions in patients Epoetin alfa e o en who will be receiving concomitant Am en, Inc chemotherapy for a minimum of 2 months.
EPOGENB is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis or gastrointestinal bleeding, which should be managed appropriately.
EPOGEN is indicated for the treatment of anemia associated with CRF, including Epoetin alfa e o en Amgeny Inch patients on dialysis (ESRD) and patients not on dialysis.
For treatment of locally advanced or erlotinib Tarceva metastatic Non Small-Cell Lung Cancer OSI
(NSCLC) after failure of at least one prior chemotherapy regimen For use in combination with gemcitabine for erlotini rceva the first-line treatment of patients with OSI
locally advanced, unresectable or metastatic -pancreatic cancer Pharmacia & Upjoh estramustine Ecvt palliation of prostate cancer Companv Management of refractory testicular tumors, etoposide phosphate Eto.pophos in combination with other approved Bristol-Myers Squil;
chemotherapeutic agents.
Management of small cell lung cancer, first-etorooside phosphate Etopophos line, in combination with other approved Bristol-Myers Squit chemotherapeutic agents.
0 oside phosphate Etopophos Management of refractory testicular tumors gristol-Mxers Squit and small cell lung cancer.
Refractory testicular tumors-in combination therapy with other approved chemotherapeutic agents in patients with etoposide. VP- 16 Ve esid refractory testicular tumors who have Bristol-Myers Squil already received appropriate surgical, chemotherapeutic and radiotherapeutic therapy.
In combination with other approved etoposide. VP-16 VePesid chemotherapeutic agents as first line Bristol-Mvers Squil treatment in patients with small cell lung http://www.accessdata.fda.gov/scripts/cder/onctools/druglist.cfm 7/21/0t List of Approved Oncology Drugs with Approved Indications Page 9 of 21 cancer.
In combination with other approved etoposide, VP-16 Ve esid chemotherapeutic agents as first line Bristol-Mvers Squil treatment in patients with small cell lung cancer, For adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three exemestane Aromasin years of tamoxifen and are switched to Pharrnacia AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy Treatment of advance breast cancer in pharmacia & Upjoh:
exemestane Aromasin postmenopausal women whose disease has Companv progressed following tamoxifen therapy.
Decrease incidence of infection in patients ~ en Inc Fil rag stim Neupogen with nonmyeloid malignancies g NEUPOGEN is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with Filgrastim Neupogen nonmyeloid malignancies receiving Am eg n, Inc myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever.
NEUPOGEN is indicated for reducing the time to neutrophil recovery and the duration Fil ragstim eu o en of fever, following induction or Arngen, Inc consolidation hemotherapy treatment of adults with AML.
NEUPOGEN is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, eg, febrile Filgrastim Neupogen neutropenia, in patients with nonmyeloid Amgen. Inc malignancies undergoing myeloablative chemotherapy fdllowed by marrow transplantation.
floxuridine FUDR Roche (intraarteriall Palliative treatment of patients with B-cell lymphocytic leukemia (CLL) who have not fludarabine Fludara responded or have progressed during Berlex Laboratories treatment with at least one standard alkylating agent containing regimen, fluorouracil, 5-FU Adrucil prolong survival in combination with ICN Puerto Rico leucovorin the treatment of hormone receptor-positive fulvestrant Faslodex metastatic breast cancer in postmenopausal IPR
women with disease progression following antiestrogen therapy Accel. Approv. (clinical benefit not established ) as monotherapy for the treatment of patients with locally advanced http://www.accessdata.fda.gov/scripts/cder/onctools/druglist.cfm 7/21/0E

List of Approved Oncology Drugs with Approved Indications Page 10 of 21 il5 or metastatic non-small cell lung cancer after gefitinib iressa failure of both platinum-based and docetaxel AstrraZenea chemotherapies Treatment of patients with locally advanced (nonresectable stage II or III) or metastatic gemcitabine emzar (stage IV) adenocarcinoma of the pancreas. Eli Lill Indicated for first-line treatment and for patients previously treated with a 5-fluorouracil-containing regimen.
For use in combination with cisplatin for the first-line treatment of patients with gemcitabine Gernzar inoperable, locally advanced (Stage IIIA or Eli Lilly IIIB) or metastatic (Stage IV) non-small cell lung cancer.
For use in combination with paclitaxe] for the first-line treatment of patients with gemicitabine Gemzar metastatic breast cancer after failure of prior Lillv anthracycline-containing adjuvant chemotherapy, unless anthraoyclines were clinically contraindicated Accel. Approv. (clinical benefit not established) Treatment of CD33 positive gemtuzumab lotar acute myeloid leukemia in patients in first W. cy th Ayerst ozog_amicin relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy.
goserelin acetate Zoladex AZeneca Phannaceutiaals goserelin acetate Zoladex Implant Palliative treatment of advanced breast Astra4eneca cancer in pre- and perimenopausal women. Phannaceuticals histrelin acetate His relin imphnt For the palliative treatment of advanced Valera prostate cancer hydroxyurea Hydrea Bristol~Myers Saiti~
hydroxvurea Hydrea Decrease need for transfasicns in sickle cell gristol-Myers Sc~uil anemia Accel. Approv. (clinical benefzt not established) treatment of patients with relapsed or refractory low-grade, follicular, IDEC Pharmaceutic Ibritumomab Tiuxetan Zevalin or transformed B-cell non-Hodgkin's Corp lymphoma, including patients with Rituximab refractory follicular non-Hodgkin's lymphoma.
For use in combination with other approved idarubicin Idamycin antileukemic drugs for the treatment of acute Adri Laboratories myaloid ]eukemia (AML) in adults.
In combination with other approved Pharmacia Upjoh idarubicin Idamycin antileukernic drugs for the treatment of acute Cornnanv no.n-lymphocytic leukemia in adults.

ifosfamide IFEX Third line chemotherapy of germ cell Bristol-Myers S uiti testicular cancer when used in combination http://www.accessdata.fda.gov/scripts/eder/onctools/druglist.cfm 7/21l0E

~ist of Approved Oncology Drugs with Approved Indications Page 11 of 21 with certain other approved antineoplastic agents.
Accel. Approv. (clinical benefit not imatinib mesylate Gleevec established) Initial therapy of chronic Novartis myelogenous leukemia Accel. Approv. (clinical benefit not imatinib mesylate Gleevec established) metastatic or unresectable Novartis malignant gastrointestinal stromal tumors Accel. Approv. (clinical benefit not established) Treatment of patients with Kit Imatinib mesylate Gleevec (CD1 17) positive unresectable and/or Novartis metastatic malignant gastrointestinal stromal tumors (GIST).
Accel. Approv. (clinical benefit not imatinib mes, ly ate Gleevec established) Initial treatment of newly Novartis diagnosed Ph+ chronic myelogenous leukemia (CML).
Accel. Approv. (clinical benefit not established) for treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) in chronic phase. Follow-up is limited. Gleevec is also indicated for the treatment of patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of imatinib mesylate Gleevec interferon-alpha therapy. There are no ovartis controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival in patients with CML blast crisis, accelerated phase or chronic phase after failure of alpha interferon. Gleevec is also indicated for the treatment of patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) Accel. Approv. (clinical benefit not established) Treatment of pediatric patients imatinib mesylate Gleevec with Ph+ chronic phase CML whose disease Navartis has recurred after stem cell transplant or who are resistant to interferon alpha therapy.
Conversion to regular approval for treatment of patients with Philadelphia chromosome imatinib mesylate Gleevec positive chronic myeloid leukemia (CML) in Novartis blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy interferon alfa 2a Roferon A Treatment of patients with hairy cell Roche leukemia Chronic phase, Philadelphia chromosome http://www. accessdata.fda. gov/scripts/eder/onctools/druglist.cfin 7/21 /0t :,ist of Approved Oncology Drugs with Approved Indications Page 12 of 21 fG;;u IL I(.II :Jl. ";,;
positive chronic myelogenous leukemia interferon alfa 2a Roferon A (CML) patients who are minimally Roc e pretreated (within 1 year of diagnosis) Interferon alfa-2a Roferon-A Hofftnann-La RochF
Interferon alfa-2b, recombinant for Injection Interferon alfa-2b Intron A is indicated for the treatment of patients 18 Scherina Corn years of age or older with hairy cell leukemia.
Interferon alfa-2b, recombinant for Injection is indicated for intralesional treatment of selected patients 18 years of age or older Interferon alfa-2b Intron A with condylomata acuminata involving Schering Cor~
external surfaces of the genital and perianal areas.
Interferon alfa-2b, recombinant for injection is indicated for the treatment of selected patients 18 years of age or older with AIDS-related Kaposi's Sarcoma. The likelihood of Interferon alfa-2b Intron A response to INTRON A therapy is greater in Schering Corp patients who are without systemic symptoms, who have limited lymphadenopathy and who have a relatively intact immune system as indicated by total CD4 count.
Interferon alfa-2b, recombinant for injection is indicated as adjuvant to surgical treatment Interferon alfa-2b Intron A in patients 18 years of age or older with Schering Corp malignant melanoma who are free of disease but at high risk for systemic recurrence within 56 days of surgery.
Interferon alfa-2b, recombinant for Injection is indicated for the initial treatment of clinically aggressive follicular non-Interferon alfa-2b Intron A Hodgkin's Lymphoma in conjunction with Schering Corp anthracycline-containing combination chemotherapy in patients 18 years of age or older.
Interferon alfa-2b Intron A Intron A Schering Co Accel. Approv. (clinical benefit subsequently established) Treatment of Pharmacia & Uvjohi irinotecan Camptosar patients with metastatic carcinoma of the CompanX
colon or rectum whose disease has recurred or progressed following 5-FU-based therapy.
Conversion to regular approval - treatment irinotecan Campo tsar of metastatic carcinoma of the colon or Pharmacia &U-pjolu rectum whose disease has recurred or Comp=
progressed following 5-FU-based therapy.
For first line treatment n combination with pharmacia & U ohi irinotecan Camptosar 5-FU/leucovorin of inetastatic carcinoma of pa the colon or rectum. Company http://www.accessdata.fda.gov/scriptslcder/onctools/druglist.cfm 7/21/06 'ist of Approved Oncology Drugs with Approved Indications Page 13 of 21 for the treatment of patients with transfusion-dependent anemia due to Low-lenalidomide Revlimid or Intermediate-l-risk myelodysplastic Celg_ene syndromes associated with a deletion 5q cytogenetic abnonnality with or without additional cytogenetic abnormalities letrozole Femara Treatment of advanced breast cancer in Novartis postmenopausal women.
First-line treatment of postmenopausal letrozole Femara women with hormone receptor positive or Novartis hormone receptor unknown locally advanced or metastatic breast cancer.
letrozole Femara Novartis Accel. Approv. (clinical benefit not established) for the extended adjuvant letrozole Femara treatment of early breast cancer in Novartis postmenopausal women who have received five years of adjuvant tamoxifen therapy.
Leucovorin calcium is indicated fro use in leucovorin Wellcovorin, combination with 5-fluorouracil to prolong Immunex Corporatic Leucovorin survival in the palliative treatment of patients with advanced colorectal cancer.
leucovorin Leucovorin Immunex Corporatic leucovorin Leucovorin Immunex Corporatic leucovorin Leucovorin Immunex Corporatic In combination with fluorouracil to prolong leucovorin Leucovorin survival in the palliative treatment of Lederle Laboratorie:
patients with advanced colorectal cancer.
Leuprolide Acetate Eli ard palliative treatment of advanced prostate LT USA
cancer.
Adjuvant treatment in combination with 5- Janssen Research levamisole Ergamisol fluorouracil after surgical resection in Foundation patients with Dukes' Stage C colon cancer.

lomustine, CCNU CeeBU Bristol-Myers Squib meclorethamine, Mustargen Merck nitrogen mustard megestrol acetate Megace Bristol-Mvers Sauib melphalan, L-PAM Alkeran G1axoSmithKline Systemic administration for palliative melphalan. L-PAM Alkeran treatment of patients with multiple myeloma G1axoSmit -.iKline for whom oral therapy is not appropriate.
mercaptopurine, 6-MP Purinethol G1axoSmithKline http-//www.accessdata.fda.gov/scripts/cder/onetools/druglist.cfm 7/21/06 List of Approved Oncology Drugs with Approved Indications Page 14 of 21 ."' u::u ;l:iG .Jl. Pa~'t.ll mesna Mesnex Prevention of ifosfamide-induced Asta Medica hemorrhagic cystitis Reducing the incidence of ifosfamide-mesna Mesnex tabs induced hemorrhagic cystitis Baxter methotrexate Methotrexate Lederle Laboratorie:
methotrexate Methotrexate Lederle Laboratorie methotrexate Methotrexate Lederle Laboratorie:
methotrexate Methotrexate Lederle Laboratoriet methotrexate Methotrexate osteosarcoma . Lederle Laboratorie:
methotrexate Methotrexate Lederle Laboratorie:
For the use of UVADEX with the UVAR
Photopheresis System in the palliative methoxsalen Uvadex treatment of the skin manifestations of Therakos cutaneous T-cell lymphoma (CTCL) that is unresponsive to other forms of treatment.
mitomycin C Mutamycin Bristol-Myers Sauib therapy of disseminated adenocarcinoma of the stomach or pancreas in proven mitomycin C Mitozytrex combinations with other approved Su ep rgen chemotherapeutic agents and as palliative treatment when other modalities have failed.
mitotane ~sodren Bristol-Myers Sauib For use in combination with corticosteroids mitoxantrone Novantrone as initial chemotherapy for the treatment of Immunex Corporatic patients with pain related to advanced hormone-refractory prostate cancer.
For use with other approved drugs in the mitoxantrone Novantrone initial therapy for acute nonlymphocytic Lederle Laboratorie., leukemia (ANLL) in adults.
nandrolone Durabolin-50 Organon hen ro ionate Accel. Approv. (clinical benefit not established) for the treatment of patients with T-cell acute lymphoblastic leukemia nelarabine Arranon and T-cell lymphoblastic lymphoma whose GlaxoSmithKline disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens Boehringer Ingelhei~
ofetumomab Verluma Pharma KG former Karl Thomae GmbH
Oprelvekin Neumeea Genetics Institute, Ir Prevention of severe thrombocytopenia --http://www_accessdata.fda.gov/scripts/eder/onctools/drugligt.cfin 7/21/06 List of Approved Oncology Drugs with Approved Indications Page 15 of 21 {( ;~ if '~ li ., ' f}..l- '.' :$ ~ .u fi in k'?' ;i ~ 1L ! 'i~ ~~,.~
following niyelosuppressive chemotherapy Neumega is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions Oprelvekin _eumega following myelosuppressive chemotherapy Genetics Institute.
Ir in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia.
Oprelvekin eumeea Genetics Institute, Ir Accel. Approv. (clinical benefit not established) in combination with infiusional 5-FU/LV, is indicated for the treatment of patients with metastatic carcinoma of the oxaliplatin Eloxatin colon or rectum whose disease has recurred Sanofi Svnthelabo or progressed during or within 6 months of completion of first line therapy with the combination of bolus 5-FU/LV and irinotecan.
Conversion to regular approval for use in combination with infusional 5-Fluorouracil oxaliplatin Eloxatin (5-FU) and Leucovorin (LV) for the Sanofi Synthelabo treatment of patients previously untreated for advanced colorectal cancer for use in combination with infusional5-FU/LV, for the adjuvant treatment of stage oxaliplatin Eloxatin III colon cancer patients who have Sanofi Synthelabo undergone complete resection of the primary tumor treatment of advanced AIDS-related Baker Norton paclitaxel Paxene Kaposi's sarcoma after failure of first line or Pharrnaceuticals. Inc subsequent systemic chemotherapy Treatment of patients with metastatic paclitaxel Taxol carcinoma of the ovary after failure of first- Bristol-Myers Squib line or subsequent chemotherapy.
Treatment of breast cancer after failure of combination chemotherapy for metastatic paclitaxel Taxol disease or relapse within 6 months of Bristol-Iv1 ers Squib adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
New dosing regimen for patients who have paclitaxel Taxol failed initial or subsequent chemotherapy for Bristol-M."."yers Squib metastatic carcinoma of the ovary paclitaxel Taxol second line therapy for AIDS related Bristol-M ers S uib Kaposi's sarcoma. ~'- ~
For first-line therapy for the treatment of paclitaxel Taxol advanced carcinoma of the ovary in B_ ristol-Mvers Squib combination with cisplatin.
for use in combination with cisplatin, for the paclitaxel Taxol first-line treatment of non-small cell lung Bristol-Mvers Squib cancer in patients who are not candidates for ittp://www.accessdata.fda.gov/scripts/eder/onctools/druglist.cfin 7/21/06 List of Approved Oncology Drugs with Approved Indications Page 16 of 21 potentially curative surgery and/or radiation therapy.
For the adjuvant treatment of node-positive naclitaxel Taxol breast cancer administered sequentially to Bristol-M _ers S
ib standard doxorubicin-containing -y- q-u -combination therapy.
paclitaxel Taxol First line ovarian cancer with 3 hour Bristol-Myers Squib infusion.
For the treatment of breast cancer after failure of combination chemotherapy for paclitaxel protein- metastatic disease or relapse within 6 bound particles Abraxane months of adjuvant chemotherapy. Prior AM Bioscience therapy should have included an anthracyline unless clinically contraindicated Decrease the incidence and duration of severe oral mucositis in patients with palifermin Kepivance hematologic malignancies receiving Amgen myelotoxic therapy requiring hematopoetic stem cell support Treatment of osteolytic bone metastases of pamidronate Aredia breast cancer in conjunction with standard ovartis antineoplastic therapy.
Adagen (Peaademase Enzyme replacement therapy for patients pegademase Bovine with severe combined immunodeficiency asa Enzen result of adenosine deaminase deficiency.
Acute lymphocytic leukemia in L-pe~asaargase Oncaspar asparaginase hypersensitive patients Enzon, Inc Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-Peafil rastim Neulasta myeloid malignancies receiving Am egn, Inc myelosuppressive anti-canaer drugs associated with a clinically significant incidence of febrile neutropenia.
For use in the treatment of patients with pemetrexed disodium Alimta malignant pleural mesothelioma whose Lil1y disease is either unresectable or who are otherwise not candidates for curative surgery Accel. Approv. (clinical benefit not established) as a single agent for the pemetrexed disodium Alimta treatment of patients with locally advanced Lillv or metastatic non-small lung cancer after prior chemotherapy Single agent treatment for adult patients with Parke-Davis pentostatin Nipent alpha interferon refractory hairy cell Pharrnaceutical Co.
leukemia.
Single-agent treatment for untreated hairy cell leukemia patients with active disease as Parke-Davis pentostatin Ninent defined by clinically significant anemia, pharmaceutical Co.
neutropenia, thrombocytopenia, or disease-related symptofns. (Supplement for front -ittp://www.accessdata.fda.gov/scriptsJcder/onctools/druglist.cfm 7/21/06 Jst of Approved Oncology Drugs with Approved Indications Page 17 of 21 rb I~ ~f 1"RY
L: line therapy.) )ipobroman Verc e Abbott Labs )Iicamycin, Mithracin Pfizer Labs nithramycin For the ablation of high-grade dysplasia in )orfimer sodium Photofrin Barrett's esophagus patients who do not Axcan Scandipharm undergo esophagectomy For use in photodynamic therapy (PDT) for palliation of patients with completely 4rfimer sodium Photofrin obstructing esophageal cancer, or patients LT
Photothera eui with partially obstructing esophageal cancer - -~
who cannot be satisfactorily treated with ND-YAG laser therapy.
For use in photodynamic therapy for treatment of microinvasive endobronchial porfimer sodium Photofrin nonsmall cell lung cancer in patients for QLT
Phototherapeui whom surgery and radiotherapy are not indicated.
For use in photodynamic therapy (PDT) for reduction of obstruction and palliation of porfimer sodium Photofrin symptoms in patients with completely or QLT
Photothera eu1 partially obstructing endobroncial nonsmall cell lung cancer (NSCLC).

procarbazine Matulane Sigma Tau Pharms quinacrine Atabrine Abbott Labs ELITEK is indicated for the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, Rasburicase Elitek and solid tumor malignancies who are Sanofi-Synthelabo, l receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.
for use in the first-line treatment of patients with diffuse large B-cell, CD20-positive, Rituximab Rituxan non-Hodgkin's lymphoma in combination Genentech, Inc with CHOP or other anthracycline-based chemotherapy regimens.
Treatrnent of patients with relapsed or Rituximab Rituxan refractory low-grade or follicular B-cell non- Genentech, Inc Hodgkin's lymphoma Acceleration of myeloid recovery following autologous bone marrow transplant in sar gramosti m Leukine patients with non-Hodgkin's lymphoma, Berlex acute lymphocytic leukemia, or Hodgkin's disease Sararamostim Prokine Immunex Corn sorafenib Nexavar For the treatment of patiwiis with advanced BM-e-r http://www.accessdata.fda.gov/scripts/cder/onctools/druglist_cfm 7/21/06 ,ist of Approved Oncology Drugs with Approved Indications Page 18 of 21 lp Ik~.,,IE' =''si:
renal cell carcinoma ;treptozocin Zanosar Antineoplastic agent. Pharmacia &~...Tp'ol Companv treatment of gastrointestinal stromal tumor iunitinib maleate Sutent after disease progression on or intolerance to Pfizer imatinib mesylate Accel. Approv. (clinical benefit not established) for the treatment of advanced renal cell carcinoma. Approval for advanced renal cell oarcinoma is based on partial sunitinib maleate Sutent response rates and duration of responses. pfizer There are no randomized trials of SUTENT
demonstrating clinical benefit such as increased survival or improvement in disease-related symptoms in renal cell carcinoma.
For the prevention of the recurrence of talc Sclerosol malignant pleural effusion in symptomatic Bryan patients.
tamoxifen Nolvadex AstraZeneca Pharmaceuticals As a single agent to delay breast cancer tarnoxifen Nolvadex recurrence following total mastectomy and AstraZeneca axillary dissection in postmenopausal Pharmaceuticals women with breast cancer (T1-3, N1, MO) For use in premenopausal women with AstraZeneca tamo 6 x Nolvadex metastatic breast cancer as an alternative to Ph ceuticals oophorectomy or ovarian irradiation tamoxifen Nolvadex For use in women with axillary node- AstraZeneca negative breast cancer adjuvant therapy. Pharmaceuticals tamoxifen Nolvadex Metastatic breast cancer in men. AstraZeneca Pharrnaceuticals Equal bioavailability of a 20 mg Nolvadex AstraZeneca tamoxifen Nolyadex tablet taken once a day to a 10 mg Nolvadex pharmaceuticals tablet taken twice a day.
tamoxifen Nolvadex to reduce the incidence of breast cancer in AstraZeneca women at high risk for breast cancer Pharmaceuticals In women with DCIS, following breast AstraZeneca tamoxifen olvadex surgery and radiation, Nolvadex is indicated pharmaceuticals to reduce the risk of invasive breast cancer.
Accel. Approv. (clinical benefit not established) Treatment of adult patients with refractory anaplastic astrocytoma, i.e., temozolomide Temodar patients at first relapse with disease Schering progression on a nitrosourea and procarbazine containing regimen Conversion to regular approval for the temozolomide Temodar treatment of patients with newly diagnosed Scherin~
high grade gliomas concomitantly with radiotherapy and then as adjuvant treatment In combination with other approved http_//www.accessdata.fda.gov/scripts/cder/onctools/druglist.cfm 7/21/0f List of Approved Oncology Drugs with Approved Indications Page 19 of 21 iI: r Il ;: "~,,.='' ~l i~ i 1{,:I! fEi'~
anticancer agents for induction therapy in teniposide, VM-26 Vumon patients with refractory childhood acute Bristol-M}~ers Squib lymphoblastic leukemia (all).
testolactone Teslac Bristol-MYers Squib testolactone Teslac Bristol-Myers Squib thioguanine, 6-TG Thio uanine G1axoSmithKline thiotepa Thionlex Immunex Corporatic thiotena Thioplex Immunex CoToratic thiotepa Thioplex Lederle Laboratorie:
Treatment of patients with metastatic topotecan H3~amtin carcinoma of the ovary after failure of initial G1axoSmithKline or subsequent chemotherapy.
Treatment of small cell lung cancer sensitive disease after failure of first-line chemotherapy. In clinical studies submitted to support approval, sensitive disease was topotecan Hycamtin defined as disease responding to G1axoSmithKline chemotherapy but subsequently progressing at least 60 days (in the phase 3 study) or at least 90 days (in the phase 2 studies) after chemotherapy toremifene Fareston Treatment of advanced breast cancer in Orion Com.
postmenopausal women.
Accel. Approv. (clinical benefit not established) Treatment of patients with Tositumomab Bexxar CD20 positive, follicular, non-Hodgkin's Corixa Corporation lymphoma, with and without transformation, whose disease is refraetory to Rituximab and has relapsed following chemotherapy xpand the indication to include patients Tositumomab/I-131 with relapsed or refractory low grade tositumomab Bexxar follicular transformed CD20-positive non- G1axoSmithKline Hodgkin's lymphoma who have not received rituximab HERCEPTIN as a single agent is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the Genentech Trastuzumab Herceptin HER2 protein and who have received one or . Ine more chemotherapy regimens for their metastatic disease.

Herceptin in combination with paclitaxel is Trastuzumab Herceptin indicated for treatment of patients with Genentech. Inc metastatic breast cancer whose tumors overexpress the HER-2 protein and had not received chemotherapy for their metastatic attp:/Iwww.accessdata.fda=gov/scriptsleder/onetools/druglist.cfrn 7/21/06 ,ist of Approved Oncology Drugs with Approved Indications Page 20 of 21 a.i!! II;,C ' 11Ø disease rrastuzumab Herceptin Genentech, Inc I'rastuzumab Hero~tin Genentech.Inc Induction of remission in patients with acute promyelooytic leukemia (APL) who are :retinoin _ATRA Vesanoid refractory to or unable to tolerate Roche anthracycline based cytotoxic chemotherapeutic regimens.
Uracil Mustard Uracil Mustard Roberts Labs Capsules For intravesical therapy of BCG-refractory carcinoma in situ (CIS) of the urinary valrubicin Valstar bladder in patients for whom immediate Anthra --> Medeva cystectomy would be associated with unacceptable morbidity or mortality.

vinblastine Velban Eli Lilly vincristine Oncovin Eli Lilly vincristine Oncovin Eli Lilly vincristine Oncovin Eli Lillv vincristine Oncovin Eli Lilly vincristine Oncovin Eli Lillv vincristine Oncovin Eli Lilly vincristine Oncovin Eli LiL1X
Single agent or in combination with cisplatin vinorelbine Navelbine for the first-line treatment of ambulatory GlaxoSmithKline patients with unresectable, advanced non-small cell lung cancer (NSCLC).
Navelbine is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unreseactable, advanced non-small cell lung vinorelbine Navelbine cancer (NSCLC). In patients with Stage IV
GlaxoSmithKline SCLC, Navelbine is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, Navelbine is indicated in combination with cisplatin.
the treatment of patients with multiple myeloma and patients with documented zoledronate Zometa bone metastases from solid tumors, in Novartis conjunction with standard antineoplastic therapy. Prostate cancer should have http://www_accessdata.fda.gov/scripts/cder/onntools/druglist.cfrn 7/21/06 -ist of Approved Oncology Drugs with Approved Indications Page 21 of 21 :!! L:' ,,... 9 ili:f progressed after treatment with at least one hormonal therapy zoledronic acid Zometa Treatment of hypercalcemia of malignancy Novartis ttp://www.accessdata.fda.gov/scripts/cder/onctools/druglist.cfrn 7121/06

Claims (63)

1. An isolated compound having the structure:

wherein A-B together represent one of the following structures:

or pharmaceutically acceptable derivative thereof;
wherein one of ---- . is a double bond, as valency permits;
R2 is hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
R4 is hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
X1A is NR1 or -C(R X1)-; wherein R1 taken together with a moiety present on L1 may form an optionally substituted heterocyclic ring;
X2A is NR3 or -C(R X1)-; wherein one of X1A and X2A is -C(R X1)-, but not both;
X1B and X2B are -N- or -C(R X1)-; whereby one of X1B and X2B is -C(R X1)-but not both;
wherein R1 and R3 are independently hydrogen, a nitrogen protecting group, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; and R X1 is hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
L1 is a 2-8 atom heteroaliphatic linker having at least one N, O or S atom in the heteroaliphatic main chain;
L2 is a 1-6 atom heteroaliphatic linker having at least one N atom in the heteroaliphatic main chain;
V is an alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; and Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
with the proviso that no occurrence of R1, R3, R4 or R X1 is Q1, Q2 or Q3, wherein Q1 is -(CR1A R1B)m C.ident.C-(CR1A R1B)t R1C, -(CR1A R1B)m C=C-(CR1A R1B)t R1C, -C=NOR1D, or -X3R1D wherein m is an integer from 0 to 3, t is an integer from 0 to 5, and X3 is a divalent group derived from azetidine, oxetane or a C3-4carbocyclic group;
Q2 is -(CR1A R1B)m C.ident.C-(CR1A R1B )k R1E, -(CR1A R1B)m C=C-(CR1A R1B)k wherein k is an integer from 1 to 3 and m is an integer from 0 to 3; and Q3 is -(CR1A R1B)t R1C, wherein t is an integer from 0 to 5 and the attachment point to R1C is through a carbon atom of the R1C group; wherein R1A
and R1B are independently H or C1-6alkyl; R1C is an optionally substituted non-aromatic monocyclic ring, a fused or bridged bycyclic ring or a spirocyclic ring; R1E
is -NR1A R1D or -OR1D; R1D is R1F, -C(=O)R1F, -SO2R1F, -C(=O)N(R1F)2, -SO2N(R1F)2, or -CO2R1F, wherein R1F is H, C1-6alkyl, -(CR1A R1B)t(C6-10aryl) or -(CR1A
R1B)t(4-10 membered heterocyclic).

2. The compound of claim 1 wherein in any one or more of the following groups, the recited variables do not occur simultaneously as defined:

(i) A-B together represent ; X1A is NR1 and X2A is CR X1 or X1A is CR X1 and X2A is NR3; L1 is X(CHR X)0-2-, wherein X is O, S, NH or NC1-4alkyl, and R X is H or C1-4alkyl; Y is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl or quinazolinyl; and L2-Z is lower alkyl (1-4 carbon atoms), cycloalkyl (3-8 carbon atoms), lower alkoxy (1-4 carbon atoms), cycloalkoxy (3-8 carbon atoms), lower perfluoroalkyl (1-4 carbon atoms), lower acyloxy (1-4 carbon atoms; -OC(O)R), amino, lower mono or dialkylamino (1-4 carbon atoms), lower mono or dicycloalkylamino (3-8 carbon atoms), hydroxymethyl, lower acyl (1-4 carbon atoms; -C(O)R), lower thioalkyl (1-4 carbon atoms), lower sulfinylalkyl (1-4 carbon atoms), lower sulfonylalkyl (1-4 carbon atoms), thiocycloalkyl (3-8 carbon atoms), sulfinylcycloalkyl (3-8 carbon atoms), sulfonylcycloalkyl (3-8 carbon atoms), sulfonamido, lower mono or dialkylsulfonamido (1-4 carbon atoms), mono or dicycloalkylsulfonamido (3-8 carbon atoms), mercapto, carboxy, carboxamido (-C(O)NH2), lower mono or dialkylcarboxamido (1-4 carbon atoms), mono or dicycloalkylcarboxamido (3-8 carbon atoms), lower alkoxycarbonyl (1-4 carbon atoms), cycloalkoxycarbonyl (3-carbon atoms), lower alkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbon atoms), lower alkynyl (2-4 carbon atoms); and (ii) A-B together represent X1A is NR1 and X2A is CR X1 or X1A is CR X1 and X2A is NR3; R X1 is hydrogen halo, nitro, C1-6alkoxy, -CONR a R b, -O(CH2)n NR a R b, -(CH2)n NR a R b or NR a R b; L1 is -NHCH2-; Y-L2-Z is pyridinyl, pyrimidinyl, indazolyl, dihydroisoindolyl, benzisoxazolyl, oxazolyl, imidazolyl, oxadiazolyl or thiazolyl each optionally substituted with halo, C1-6alkyl, C1-6alkoxy, -O(CH2)n NR x R y, -O(CH2)n OR x, NR x R y, -(CH2)n NR x R y, -CH2OR x, -COOR x, -CONR x R y, -CH2SO2NR x R y, -SO2NR x R y, or optionally substituted phenyl;
and R2 is pyridin-2-yl, C1-6alkylpyridin-2-yl, C1-6alkylpyrrol-2-yl or C1-6alkylthiazol--2-yl; wherein R a is H or C1-4alkyl, R b is C1-4alkyl, or R a and R b together for a 3-7-membered heterocyclic ring; and R x and R y are independently H or C1-6alkyl.

3. The compound of claim 1 having the structure:

4. The compound of claim 1 having the structure:

wherein A-B together represent one of the following structures:

wherein W1 is O or NR W1, where R W1 is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and Alk1 is a 6alkylene or C2-6alkenylene moiety; W2 and W3 are independently absent, O, NR
W, CR W1R W2 or NR W CR W1R W2, where R W is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl; and R W1 and R
W2 are independently hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic; with the proviso that W2 and W3 are not each absent and at least one of W2 and W3 is NR W or NR W CR W1R W2; or R W1 taken together with a carbon atom present on Alk1 may form a heterocyclic moiety.

5. The compound of claim 1 having the structure:

wherein R1, R3, R4, L2, Y and Z are as defined in claim 1; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(-O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR L1B-, -O-, -S-, or -NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl.

6. The compound of claim 1 having the structure:

wherein R1, R3, R4, L1, Y and Z are as defined in claim 1; G2 is absent, O or NR G2; and R W2 and R G2 are independently hydrogen, lower alkyl, lower heteroalkyl;
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.

7. The compound of claim 1 having the structure:

wherein R1, R3, L4, Y and Z are as defined in claim 1; and R W2, R W3 and R W4 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl.

8. The compound of claim 1 having the structure:

wherein q is an integer from 0-2; R1, R3, R4, L1, L2 and Z are as defined in claim 1; and J1, J2 and J3 are independently O, S, N, NR Y1 or CR Y1; wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -C)R Y3, -SR Y3, -NR Y2 R Y3, -SO2NR Y2R
Y3, -C(=O)NR Y2R Y3, halogen, -CN, NO2, -C(=O)OR Y3, -N(R Y2}C(=O)R Y3, wherein each occcurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R
Y2 and R Y3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.

9. The compound of claim 8 having the structure:

10. The compound of claim 1 having the structure:

wherein q is an integer from 0-3; R1, R3, R4, L1, L2 and Z are as defined in claim 1; and J4, J5 and J6 are independently N or CR Y1; wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Y3, -SR Y3, -NR Y2R Y3, -SO2NR Y2R Y3, -C(-O)NR Y2R Y3, halogen, -CN, NO2, -C(=O)OR Y3, -N(R Y2)C(=O)R Y3, wherein each occcurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Y2 and R Y3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.

11. The compound of claim 11 having the structure:

12. The compound of claim 11 having the structure:

13. The compound of claim 1 having the structure:

wherein R1, R3, R4, L2 and Z are as defined in claim 1; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(-O)-, -NR L1A C(=O)-, -NR L1A
CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR
L1B-, -O-, -S-, or -NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3; J1, J2 and J3 are independently O, S, N, NR Y1 or CR Y1;
J4, J5 and J6 are independently N or CR Y1; wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Y3, -SR Y3, -NR Y2R Y3, -SO2NR Y2R Y3, -C(=O)NR Y2R Y3, halogen, -CN, -NO2, -C(=O)OR Y3, N(R Y2)C(=O)R Y3, wherein each occcurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Y2 and R Y3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring.

14. The compound of claim 1 having the structure:

wherein R1, R3, R4 and Z are as defined in claim 1; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(-O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(-O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A
CO2-, -NR L1A C(-O)NR L1B, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR
L1B-, -O-, -S-, or -NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3; J1, J2 and J3 are independently O, S, N, NR Y1 or CR Y1;
wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Y3, -SR Y3, -NR Y2R Y3, -SO2NR Y2R Y3, -C(=O)NR Y2R Y3, halogen, -CN, -NO2, -C(=O)OR Y3, -N(R Y2)C(=O)R Y3, wherein each occcurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Y2 and R Y3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; G2 is absent, O
or NR G2; and R W2 and R G2 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.

15. The compound of claim 1 having the structure:

wherein R1, R3, R4 and Z are as defined in claim 1; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk2 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A-NR L1B C(=O)-, NR L1A C(=O)-, -NR L1A
CO2-, NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR
L1B-, -O-, -S-, or -NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3; J1, J2 and J3 are independently O, S, N, NR Y1 or CR Y1;
wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Y3, -SR Y3, -NR Y2R Y3, -SO2NR Y2R Y3, -C(=O)NR Y2R Y3, halogen, -CN, NO2, -C(=O)OR Y3, -N(R Y2)C(=O)R Y3, wherein each occcurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Y2 and R Y3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; and R W2, R W3 and R W4 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.

16. The compound of claim 1 having the structure:

wherein R1, R3, R4 and Z are as defined in claim 1; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A
CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR
L1B-, -O-, -S-, or NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3; J4, J5 and J6 are independently N or CR Y1; wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Y3, -SR Y3, -NR Y2R Y3, -SO2NR Y2R Y3, -C(=O)NR Y2R Y3, halogen, -CN, NO2, -C(=O)OR Y3, -N(R Y2)C(=O)R Y3, wherein each occcurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R
Y2 and R Y3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; G2 is absent, O or NR G2; and R W2 and R G2 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.

17. The compound of claim 1 having the structure:

wherein R1, R3, R4 and Z are as defined in claim 1; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A CO2-, -NR L1AC(=O)NR1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR L1B-, -O-, -S-, or NR L1A-;
wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an integer from 0-3;
J4, J5 and J6 are independently N or CR Y1; wherein each occurrence of R Y1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Y3, -SR Y3, -NR Y2R Y3, -SO2NR Y2R Y4, -C(-O)NR Y2R Y3, halogen, -CN, -NO2, -C(=O)OR Y3, -N(R Y2)C(=O)R Y3, wherein each occcurrence of R Y2 and R Y3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Y2 and R Y3 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring;
and R W2, R W3 and R W4 are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.

18. The compound of claim 1 having the structure:

wherein R1, R3, R4 and R X1 are as defined in claim 1; Z is an aryl, heteroaryl or heterocyclic moiety; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2 NR L1A-, -NR L1A SO2NR L1B-, -O-, -S-, or -NR L1A-;
wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR
Z2, NR Z2R Z3, -SO2N R Z2R Z3, -SO2R Z1, -C(=O)NR Z2R Z3, halogen, -CN, -NO2, -C(=O)OR Z3, -N(R Z2)C(=O)R Z3, wherein each occcurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

19. The compound of claim 1 having the structure:

wherein R1, R3, R4 and R X1 are as defined in claim 1; W1 is 0 or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, NR L1A C(=O)-, -NR L1A
CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR
L1B-, -O-, -S-, or -NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR Z2, -NR Z2R Z3, -SO2R Z1, -C(=O)NR Z2 R Z3, halogen, -CN, NO2, -C(=O)OR Z3, -N(R Z2)C(=O)R Z3, wherein each occcurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

20. The compound of claim 19 having the structure:

wherein R Z1 is halogen, lower alkyl or lower haloalkyl.

21. The compound of claim 19 having the structure:

wherein R1, R3 and R4 are independently hydrogen, lower alkyl or. -CO2R1A
where R1A is hydrogen or lower alkyl; R X1 is hydrogen, lower alkyl or heterocyclyl;
and R Z1 is halogen, lower alkyl or lower haloalkyl.

22. The compound of claim 20 or 21 wherein R Z1 is Cl, F, methyl or -CF3.

23. The compound of claim 1 having the structure:

wherein R1, R3, R4 and R X1 are as defined in claim 1; W1 is O or N R W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A
CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR
L1B-, -O-, -S-, or -NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR Z2, -NR Z2R Z3, -SO2NR Z2R Z3, -SO2 R Z1,-C(=O)NR Z2 R Z3, halogen, -CN, -NO2, -C(=O)OR Z3, -N(R Z2)C(=O)R Z3, wherein each occcurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

24. The compound of claim 23 having the structure:

25. The compound of claim 23 having the structure:

wherein R1, R3 and R4 are independently hydrogen, lower alkyl or -CO2R1A
where R1A is hydrogen or lower alkyl; and R X1 is hydrogen, lower alkyl or heterocyclyl.

26. The compound of claim 1 having the structure:

wherein R1, R3, R4 and R X1 are as defined in claim 1; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, NR L1A C(=O)-, -NR L1A
CO2-, -NR L1A C(=O)NR L1B-, -S(-O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR
L1B-, -O-, -S-, or -NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR Z2, -NR Z2R Z3, -SO2NR Z2R Z3, -SO2R Z1, -C(=O)NR Z2R Z3, halogen, -CN, -NO2, -C(=O)OR Z3, -N(R Z2)C(=O)R Z3, wherein each occcurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

27. The compound of claim 26 having the structure:

wherein R Z1 and R Z2 are independently halogen, lower alkyl or lower haloalkyl.

28. The compound of claim 26 having the structure:

wherein R1, R3 and R4 are independently hydrogen, lower alkyl or -CO2R1A
where R1A is hydrogen or lower alkyl; R X1 is hydrogen, lower alkyl or heterocyclyl;
and R Z1 and R Z2 are independently halogen, lower alkyl or lower haloalkyl.

29. The compound of claim 27 or 28 wherein R Z1 and R Z2 are each Cl, F, methyl or -CF3.

30. The compound of claim 1 having the structure:

wherein R1, R3, R4 and R X1 are as defined in claim 1; W1 is O or NR W1, where R W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A
CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR
L1B-, -O-, -S-, or NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from I to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR Z2, -NR Z2R Z3, -SO2NR Z2R Z3, -SO2R Z1, -C(=O)NR Z2R Z3, halogen, -CN, -NO2, -C(=O)OR Z3, N(R Z2)C(=O)R Z3, and wherein each occcurrence of R Z2, R Z3 and R Z4 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

31. The compound of claim 30 having the structure:

wherein RZ1 and RZ2 are independently halogen, lower alkyl or lower haloalkyl and RZ4 is lower alkyl.

32. The compound of claim 30 having the structure:

wherein R1, R3 and R4 are independently hydrogen, lower alkyl or -CO2R1A
where R1A is hydrogen or lower alkyl; R X1 is hydrogen, lower alkyl or heterocyclyl;
R Z1 and R Z2 are independently halogen, lower alkyl or lower haloalkyl and R
Z4 is hydrogen or lower alkyl.

33. The compound of claim 31 or 32 wherein R Z1 and R Z2 are each Cl, F, methyl or -CF3.

34. The compound of claim 31 or 32 wherein R Z4 is hydrogen or isopropyl.

35. The compound of claim 1 having the structure:

wherein R X1 are as defined in claim 1; R1 and R W1 taken together form an optionally substituted 5- to 6-membered ring; Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, NR L1A NR L1B C(-O)-, -NR L1A C(=O)-, -NR L1A CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR L1B-, -O-, -S-, or NR L1A-; wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR Z2, -NR Z2R Z3, -SO2NR Z2R Z3, -SO2R Z1, -C(=O)NR Z2R Z3, halogen, -CN, -NO2, -C(=O)OR Z3, -N(R Z2)C(=O)R Z3, wherein each occurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

36. The compound of claim 35 having the structure:
wherein R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; and R Z1 is hydrogen, halogen, lower alkyl or lower haloalkyl.

37. The compound of claim 36 wherein R and R Z1 are each hydrogen.

38. The compound of claim 1 having the structure:

wherein R X1 is as defined generally and in classes and subclasses herein; R1 and R W1 taken together form an optionally substituted 5- to 6-membered ring;
Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, NR L1A SO2NR L1B-, -O-, -S-, or -NR L1A-;
wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR
Z2, -NR Z2R Z3, -SO2NR Z2R Z3, -SO2R Z1, -C(=O)NR Z2R Z3, halogen, -CN, -NO2, -C(=O)OR Z3, -N(R Z2)C(=O)R Z3, wherein each occcurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

39. The compound of claim 38 having the structure:
wherein R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; R X1 is hydrogen, methyl or thienyl and R Z1 is hydrogen, halogen, lower alkyl or lower haloalkyl.

40. The compound of claim 1 having the structure:
wherein R X1 is as defined generally and in classes and subclasses herein; R1 and R W1 taken together form an optionally substituted 5- to 6-membered ring;
Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR L1B-, -O-, -S-, or -NR L1A-;
wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR
Z2, -NR Z2R Z3, -SO2NR Z2R Z3, -SO2R Z1, -C(=O)NR Z2R Z3, halogen, -CN, -NO2, -C(=O)OR Z3, -N(R Z2)C(-O)R Z3, wherein each occcurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

41. The compound of claim 40 having the structure:
wherein R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; and R X1 is hydrogen, methyl or thienyl.

42. The compound of claim 1 having the structure:
wherein R X1 is as defined generally and in classes and subclasses herein; R1 and R W1 taken together form an optionally substituted 5- to 6-membered ring;
Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(=O)-, -C(=O)NR L1A-, -OC-(-O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A CO2-, -NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR L1B-, -O-, -S-, or -NR L1A-;
wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR
Z2, -NR Z2R Z3, -SO2NR Z2R Z3, -SO2R Z1, -C(=O)NR Z2R Z3, halogen, -CN, -NO2, -C(=O)OR Z3, N(R Z2)C(=O)R Z3, wherein each occcurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

43. The compound of claim 42 having the structure:
wherein R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; R X1 is hydrogen, methyl or thienyl and R Z1 is hydrogen, halogen, lower alkyl or lower haloalkyl.

44. The compound of claim 1 having the structure:
wherein R X1 is as defined generally and in classes and subclasses herein; R1 and R W1 taken together form an optionally substituted 5- to 6-membered ring;
Alk1 is a substituted or unsubstituted C1-6alkylene or C2-6alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by -C(=O)-, -CO2-, -C(=O)C(-O)-, -C(-O)NR L1A-, -OC(=O)-, -OC(=O)NR L1A-, -NR L1A NR L1B-, -NR L1A NR L1B C(=O)-, -NR L1A C(=O)-, -NR L1A CO2-, NR L1A C(=O)NR L1B-, -S(=O)-, -SO2-, -NR L1A SO2-, -SO2NR L1A-, -NR L1A SO2NR L1B-, -O-, -S-, or -NR L1A-;
wherein each occurrence of R L1A and R L1B is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an integer from 0 to 3; r is an integer from 1 to 4; each occurrence of R Z1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, -OR Z2, -SR
Z2, -NR Z2R Z3, -SO2NR Z2R Z3, -SO2R Z1, -C(=O)NR Z2R Z3, halogen, -CN, NO2, -C(=O)OR Z3, -N(R Z2)C(=O)R Z3, wherein each occcurrence of R Z2 and R Z3 is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2 and R Z3 taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring.

45. The compound of claim 44 having the structure:
wherein R is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy; R X1 is hydrogen, methyl or thienyl and R Z1 is hydrogen, halogen, lower alkyl or lower haloalkyl.

46. The compound of claim 13, 14 or 15 wherein the 5-membered ring having the structure:

has one of the following structures:

47. The compound of claim 13, 16 or 17 wherein the 6-membered ring having the structure:

has one of the following structures:

48. The compound of claim 6, 13, 14, 15, 16, 17 or 18 wherein -W1-Alk1- is -NH-C1-6alkyl- or -O-C1-6alkyl-; wherein the C1-6alkyl moiety may be substituted or unsubstituted.

49. The compound of claim 48 wherein -W1-Alk1- is -NHCH2CH2-, -OCH2CH2- or NH-CH2CH(CH2OH)-.

50. The compound of claim 7, 14 or 16 wherein -N(R W2)C(=O)G2- is -NHC(=O)-, NHC(=O)O-, or NHC(=O)NH-.

51. The compound of claim 50 wherein -N(R W2)C(=O)G2 is NHC(=O)NH-.

52. The compound of claim 8, 15 or 17 wherein N(R W2)C(=O)N(R W2)CR W3R W4- is NHC(=O)NHCH2-, and CR W3R W4C(=O)N(R W2)- is -CH2C(=O)NH-.

53. The compound of claim 1, wherein Z has one of the following structures:
wherein each occurrence of R Z1 is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl.

54. The compound of claim 1, wherein Z has one of the following structures:

wherein R Z1 is Cl, F, methyl or CF3; and R Z4 is hydrogen or cyano.

55. The compound of any one of claims 1-54 wherein R1, R3 and R4 are independently hydrogen or lower alkyl.

56. The compound of claim 55 wherein R1, R3 and R4 are independently hydrogen, methyl, ethyl, isopropyl or one of:

wherein R1A
and R1B are independently hydrogen, methyl or ethyl.

57. A composition comprising an effective amount of compound of any one of claims 1-56, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

58. The composition of claim 57, wherein the compound is in an amount to detectably inhibit Aurora protein kinase activity.

59. The composition of claim 57, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

60. A method of inhibiting Aurora kinase activity in:
(a) a subject; or (b) a biological sample;
which method comprises administering to said patient, or contacting said biological sample with:
a) a composition of claim 57; or b) a compound of any one of claims 1-56.

61. The method of claim 60, wherein the method comprises inhibiting Aurora kinase activity.

62. A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient:
a) a composition of claim 57; or b) a compound of any one of claims 1-56.

63. The method according to claim 62, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:
said additional therapeutic agent is appropriate for the disease being treated;
and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.